Use of GLP-1 receptor agonists in treatment of neurodegenerative diseases or disorders

Abstract

A method of treating a neurodegenerative disease or condition comprising administering to a subject in need thereof a GLP-1 receptor agonist or a composition thereof, a medicament or composition using the GLP-1 receptor agonist, or a method of treatment, the traditional Chinese medicine composition can significantly improve the behavioral abilities, such as learning memory, life self-care, movement and emotion, related to neurodegenerative diseases or symptoms of a subject, and also improve the pathological states, such as brain A beta plaque deposition, nerve fiber entanglement and nerve cell inflammation, of the subject.

Description

Use of GLP-1 receptor agonists in the treatment of neurodegenerative diseases or conditions Technical Field

[0001] The present application relates to the field of medical technology, and in particular to the use of a GLP-1 receptor agonist or a composition thereof in the preparation of a medicament for treating neurodegenerative diseases or disorders. Background Art

[0002] Among the top 10 causes of death announced by the WHO, Alzheimer's disease (AD) has ranked 7th. AD is the most common type of dementia and the most expensive, deadly, and socially burdensome neurodegenerative disease of this century. Currently, there are only two types of drugs approved by the FDA for the treatment of AD: acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine; and NMDA antagonists, such as memantine. However, these drugs cannot delay the course of AD, nor can they prevent AD, let alone cure AD. Their main function is to control symptoms within one year of taking them, slowing the rate of decline in patients' thinking and memory, thereby reducing the workload of caregivers. In addition, the side effects of the drugs are severe, which also brings new pain to AD patients.

[0003] Based on this, major pharmaceutical companies have begun researching AD drugs, such as those targeting synaptic protection, neuroinflammation, metabolism, oxidative stress, and the gut microbiome. Studies have shown a close relationship between high blood sugar levels and cognitive decline, and that type 2 diabetes (T2D) can increase the risk of AD by 2-fold. Consequently, drugs used to treat T2D, ranging from insulin and metformin to dipeptidyl peptidase-4 and glucagon-like peptide receptor agonists, have also begun to be tested for AD treatment and have made progress. These include the GLP-1 agonists liraglutide and semaglutide.

[0004] However, obtaining drugs with clear therapeutic or improvement effects on AD indications remains a difficult problem that needs to be solved urgently.

[0005] Summary of the Invention

[0006] To address the deficiencies in the prior art, the present application provides a method for treating neurodegenerative diseases or conditions, comprising administering a GLP-1 receptor agonist or a composition thereof to a subject in need thereof. The use of the GLP-1 receptor agonist drug, composition, or treatment method provided herein can significantly improve the subject's behavioral abilities such as learning and memory, self-care, movement, and emotion related to neurodegenerative diseases or symptoms, while also improving pathological conditions such as Aβ plaque deposition, neurofibrillary tangles, and nerve cell inflammation in the subject's brain.

[0007] The technical solution of this application is as follows:

[0008] 1. A method for treating a neurodegenerative disease or disorder, comprising administering a GLP-1 receptor agonist or a composition thereof to a subject in need thereof; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis, or neurogliopathy; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia, or neurogliopathy.

[0009] 2. The method of claim 1 , wherein the neurodegenerative disease is Parkinson's disease.

[0010] 3. The method of claim 1 , wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

[0011] 4. The method according to claim 1 or 3, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ.

[0012] 5. The method according to any one of items 1 to 4, comprising administering to a subject in need thereof an effective amount of a GLP-1 receptor agonist or a composition thereof to block or reduce the activation of resident innate immune cells.

[0013] 6. The method according to any one of items 1 to 5, which comprises inhibiting the activation of immune cells by abnormally aggregated proteins by using a GLP-1 receptor agonist or a composition thereof.

[0014] 7. The method according to any one of items 1 to 6, wherein the amount of the GLP-1 receptor agonist or the composition thereof is effective to inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

[0015] 8. The method according to any one of items 1 to 7, wherein the innate immune cells are microglia and / or astrocytes.

[0016] 9. The method according to any one of items 1 to 8, wherein the abnormally aggregated protein is Aβ protein or Tau protein.

[0017] 10. The method according to any one of items 1 to 9, wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog, or a derivative thereof, preferably the GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

[0018] 11. The method according to any one of items 1 to 10, wherein the GLP-1 receptor agonist or a composition thereof is administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intraosseously, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, and subcutaneously.

[0019] 12. A method according to any one of items 1 to 11, wherein the derivative of the GLP-1 polypeptide analogue or a composition thereof is administered subcutaneously; preferably, it is administered in the form of a solution or suspension, and optionally in the form of a solution comprising at least 90% water and having a pH in the range of 7.0-9.0.

[0020] 13. The method according to any one of items 1 to 12, wherein the GLP-1 receptor agonist or its composition is administered in a form selected from the group consisting of a pill, a capsule, a tablet, a granule, a powder, a salt, a crystal, a liquid, a slurry, a syrup, a suspension, a gel, a cream, a paste, a film, a patch and a vapor.

[0021] 14. The method according to any one of items 1 to 11 or item 13, wherein the GLP-1 receptor agonist or the composition thereof is administered orally, preferably in the form of a tablet.

[0022] 15. The method according to any one of items 1 to 11 or items 13-14, wherein the GLP-1 receptor agonist or composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as a NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I):

[0023] Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II):

[0024] 16. The method according to any one of items 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 15 times per month.

[0025] 17. The method according to any one of items 1 to 16, wherein the GLP-1 receptor agonist or the composition thereof is administered once a week.

[0026] 18. The method according to any one of items 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 6 times per year.

[0027] 19. The method according to any one of items 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered once a month.

[0028] 20. The method according to any one of items 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered once every two months.

[0029] 21. The method according to any one of items 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered 1-2 times per day.

[0030] 22. The method according to any one of items 1 to 21, wherein the GLP-1 receptor agonist or the composition thereof has an in vivo half-life of 12 to 200 hours in non-human primates or humans.

[0031] 23. The method according to any one of items 1 to 22, wherein the GLP-1 receptor agonist or its composition is administered at a dosage of 0.001 mg / kg / subject to 100 mg / kg / subject; or a single dose of a drug comprising a GLP-1 receptor agonist or its composition can be provided to the subject at 0.001 mg / kg to 100 mg / kg.

[0032] 24. The method according to any one of items 1 to 23, wherein the GLP-1 receptor agonist or its composition is administered at a dosage of 0.001 mg / kg / subject to 10 mg / kg / subject; or a single dose of a drug comprising a GLP-1 receptor agonist or its composition can be provided to a subject at 0.001 mg / kg to 10 mg / kg.

[0033] 25. The method according to any one of items 1 to 24, wherein the GLP-1 receptor agonist or a composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

[0034] 26. The method according to any one of items 1 to 25, wherein the GLP-1 receptor agonist or composition thereof protects the subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

[0035] 27. The method according to any one of items 1 to 26, wherein the GLP-1 receptor agonist or a composition thereof can protect the subject from the effects induced by elevated Aβ protein and / or Tau protein in neurons.

[0036] 28. The method according to any one of items 1 to 27, wherein the GLP-1 receptor agonist or composition thereof protects the subject from the effects induced by GFAP elevation.

[0037] 29. The method according to any one of items 1 to 28, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

[0038] 30. A method according to any one of items 1 to 29, wherein relative to a control, in the subject, synapses and / or synaptic function are protected, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced and chronic inflammatory responses are prevented.

[0039] 31. The method according to any one of items 1 to 30, wherein the GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

[0040] 32. Use of a pharmaceutically effective amount of a GLP-1 receptor agonist or a composition thereof in the preparation of a medicament for treating a neurodegenerative disease or disorder; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis or neurogliosis; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia or neurogliosis.

[0041] 33. Use according to item 32, wherein the neurodegenerative disease is Parkinson's disease.

[0042] 34. Use according to item 32, wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

[0043] 35. The use according to claim 32 or 34, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ.

[0044] 36. The use according to any one of items 32 to 35, comprising administering to a subject in need thereof an effective amount of a GLP-1 receptor agonist or a composition thereof to block or reduce the activation of resident innate immune cells.

[0045] 37. The use according to any one of items 32 to 36, comprising inhibiting the activation of immune cells by abnormally aggregated proteins by a GLP-1 receptor agonist or a composition thereof.

[0046] 38. The use according to any one of items 32 to 37, wherein the amount of the GLP-1 receptor agonist or the composition thereof can effectively inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

[0047] 39. The use according to any one of items 32 to 38, wherein the innate immune cells are microglia and / or astrocytes.

[0048] 40. The use according to any one of items 32 to 39, wherein the abnormally aggregated protein is Aβ protein or Tau protein.

[0049] 41. The use according to any one of items 32 to 40, wherein the GLP-1 receptor agonist or its composition comprises wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog or a derivative thereof, preferably the GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

[0050] 42. The use according to any one of items 32 to 41, wherein the GLP-1 receptor agonist or its composition is administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intraosseously, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, and subcutaneously.

[0051] 43. The use according to any one of items 32 to 42, wherein the derivative of the GLP-1 polypeptide analogue or a composition thereof is administered subcutaneously; preferably, in the form of a solution or suspension, and optionally in the form of a solution comprising at least 90% water and having a pH in the range of 7.0-9.0.

[0052] 44. The use according to any one of items 32 to 43, wherein the GLP-1 receptor agonist or its composition is administered in a form selected from the group consisting of pills, capsules, tablets, granules, powders, salts, crystals, liquids, slurries, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

[0053] 45. The use according to any one of items 32 to 42 or item 44, wherein the GLP-1 receptor agonist or the composition thereof is administered orally, preferably in the form of a tablet.

[0054] 46. ​​The use according to any one of items 32 to 42 or items 44-45, wherein the GLP-1 receptor agonist or composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I):

[0055] Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II):

[0056] 47. The use according to any one of items 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 15 times per month.

[0057] 48. The use according to any one of items 32 to 47, wherein the GLP-1 receptor agonist or the composition thereof is administered once a week.

[0058] 49. The use according to any one of items 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 6 times per year.

[0059] 50. The use according to any one of items 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered once a month.

[0060] 51. The use according to any one of items 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered once every two months.

[0061] 52. The use according to any one of items 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 1-2 times a day.

[0062] 53. The use according to any one of items 32 to 52, wherein the GLP-1 receptor agonist or the composition thereof has an in vivo half-life of 12 to 200 hours in non-human primates or humans.

[0063] 54. The use according to any one of items 32 to 53, wherein the dosage of the GLP-1 receptor agonist or its composition is 0.001 mg / kg / subject-100 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or its composition can be provided to the subject at 0.001 mg / kg-100 mg / kg.

[0064] 55. The use according to any one of items 32 to 54, wherein the dosage of the GLP-1 receptor agonist or its composition is 0.001 mg / kg / subject-10 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or its composition can be provided to the subject at 0.001 mg / kg-10 mg / kg.

[0065] 56. The use according to any one of items 32 to 55, wherein the GLP-1 receptor agonist or a composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

[0066] 57. The use according to any one of items 32 to 56, wherein the GLP-1 receptor agonist or the composition thereof can protect a subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

[0067] 58. The use according to any one of items 32 to 57, wherein the GLP-1 receptor agonist or the composition thereof can protect the subject from the effects induced by the increase of Aβ protein and / or Tau protein in neurons.

[0068] 59. The use according to any one of items 32 to 58, wherein the GLP-1 receptor agonist or the composition thereof can protect the subject from the effects induced by GFAP elevation.

[0069] 60. Use according to any one of items 32 to 59, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

[0070] 61. The use according to any one of items 32 to 60, wherein relative to a control, in the subject, synapses and / or synaptic function are protected, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced and chronic inflammatory responses are prevented.

[0071] 62. The use according to any one of items 32 to 61, wherein the GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

[0072] 63. A pharmaceutically effective amount of a GLP-1 receptor agonist or a composition thereof for treating a neurodegenerative disease or disorder; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis or neurogliopathy; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia or neurogliopathy.

[0073] 64. A GLP-1 receptor agonist or composition thereof according to claim 63, wherein the neurodegenerative disease is Parkinson's disease.

[0074] 65. A GLP-1 receptor agonist or composition thereof according to claim 63, wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

[0075] 66. A GLP-1 receptor agonist or composition thereof according to claim 63 or claim 65, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ.

[0076] 67. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 66, comprising administering to a subject in need thereof an effective amount of the GLP-1 receptor agonist or composition thereof to block or reduce the activation of resident innate immune cells.

[0077] 68. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 67, wherein the GLP-1 receptor agonist or composition thereof inhibits activation of immune cells by abnormally aggregated proteins.

[0078] 69. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 68, wherein the amount of the GLP-1 receptor agonist or composition thereof can effectively inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

[0079] 70. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 69, wherein the innate immune cells are microglia and / or astrocytes.

[0080] 71. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 70, wherein the abnormally aggregated protein is Aβ protein or Tau protein.

[0081] 72. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 71, wherein the GLP-1 receptor agonist or composition thereof comprises wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog, or a derivative thereof, preferably the GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

[0082] 73. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 72, wherein the GLP-1 receptor agonist or composition thereof is administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intraosseously, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, and subcutaneously.

[0083] 74. A GLP-1 receptor agonist or composition thereof according to any one of items 63 to 73, wherein the derivative of the GLP-1 polypeptide analogue or the composition thereof is administered subcutaneously; preferably, in the form of a solution or suspension, and optionally in the form of a solution comprising at least 90% water and having a pH in the range of 7.0-9.0.

[0084] 75. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 74, wherein the GLP-1 receptor agonist or composition thereof is administered in a form selected from one of the following: pills, capsules, tablets, granules, powders, salts, crystals, liquids, slurries, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

[0085] 76. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 75, wherein the GLP-1 receptor agonist or composition thereof is administered orally, preferably in the form of a tablet.

[0086] 77. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 73 or items 75 to 76, wherein the GLP-1 receptor agonist or composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I):

[0087] Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II):

[0088] 78. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered 2 to 15 times per month.

[0089] 79. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 78, wherein the GLP-1 receptor agonist or composition thereof is administered once a week.

[0090] 80. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered 2 to 6 times per year.

[0091] 81. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered once a month.

[0092] 82. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered once every two months.

[0093] 83. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered 1-2 times per day.

[0094] 84. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 83, wherein the GLP-1 receptor agonist or composition thereof has an in vivo half-life in non-human primates or humans of 12 to 200 hours.

[0095] 85. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 84, wherein the dosage of the GLP-1 receptor agonist or composition thereof is 0.001 mg / kg / subject-100 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or composition thereof can be provided to the subject at 0.001 mg / kg-100 mg / kg.

[0096] 86. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 85, wherein the dosage of the GLP-1 receptor agonist or composition thereof is 0.001 mg / kg / subject-10 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or composition thereof can be provided to the subject at 0.001 mg / kg-10 mg / kg.

[0097] 87. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 86, wherein the GLP-1 receptor agonist or composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

[0098] 88. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 87, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

[0099] 89. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 88, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects induced by elevated Aβ protein and / or Tau protein in neurons.

[0100] 90. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 89, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects induced by an increase in GFAP.

[0101] 91. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 90, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

[0102] 92. A GLP-1 receptor agonist or composition thereof according to any one of items 63 to 91, wherein relative to a control, in the subject, synapses and / or synaptic function are protected, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced and chronic inflammatory responses are prevented.

[0103] 93. The GLP-1 receptor agonist or composition thereof according to any one of items 63 to 92, wherein the GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

[0104] Compared with the prior art, the beneficial effects of the present application are as follows: the present application provides a drug or composition containing a GLP-1 receptor agonist, especially a drug or composition containing the GLP-1 receptor agonist ecnoglutide described in the present application, and a method of using the drug or composition to treat neurodegenerative diseases or conditions. The drug or composition or treatment method using the GLP-1 receptor agonist provided by the present application can significantly improve the subject's behavioral abilities such as learning and memory, self-care, movement and emotion related to neurodegenerative diseases or symptoms, and at the same time improve the subject's pathological conditions such as Aβ plaque deposition, neurofibrillary tangles, and nerve cell inflammation in the brain. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 shows the results of the water maze test before drug administration, wherein, in Figure 1, A, the latency time for the animal to find the platform during the training period; B, the swimming speed of the animal during the training period; C, the number of times the animal found the platform during the test period; D, the time when the animal first found the platform during the test period; E, the time ratio of the animal in the target quadrant during the test period;

[0106] Figure 2 shows the results of the water maze test after 6 months of drug administration, wherein, in Figure 2, A, the latency time for the animal to find the platform during the training period; B, the swimming speed of the animal during the training period; C, the number of times the animal found the platform during the test period; D, the time when the animal first found the platform during the test period; E, the time ratio of the animal in the target quadrant during the test period;

[0107] FIG3 shows the results of the active avoidance test 7 months after drug administration;

[0108] FIG4 shows the nesting behavior test results, wherein FIG4A, nesting score before drug administration; B, nesting score 6 months after drug administration;

[0109] FIG5 shows the results of the open field test before drug administration, wherein, in FIG5 , A, total distance the animals move; B, number of times the animals cross the center;

[0110] FIG6 shows the results of the open field test after 3 months of drug administration, wherein in FIG6 , A, total distance the animals move; B, number of times the animals cross the center;

[0111] FIG7 shows the amyloid plaque area after immunohistochemical staining of brain tissue sections of experimental animals, wherein, in FIG7 , A, amyloid protein plaque area; B, Aβ 1-40 Plaque area; C, Aβ 1-42 plaque area;

[0112] FIG8 shows the plaque results of experimental animal brain tissue sections after immunohistochemical staining, wherein FIG8A shows the amyloid plaque results, and FIG8B shows the β 1-40 Plaque results, Figure 8C is β 1-42 plaque results;

[0113] FIG9 shows the results of ELISA detection of Tau protein in brain tissue of experimental animals;

[0114] Figure 10 A and B show Aβ in the brain tissue of experimental animals, respectively. 1-40 , Aβ 1-42 Liquid chip test results;

[0115] Figure 11 (A) and (B) show the quantitative results of GFAP immunohistochemical staining in the cortex and hippocampus of experimental animals, respectively;

[0116] FIG12 shows the results of GFAP immunohistochemical staining of the cortex of experimental animals;

[0117] FIG13 shows the results of GFAP immunohistochemical staining of the hippocampus of experimental animals;

[0118] Figure 14 shows the results of animal weight changes;

[0119] Figure 15 shows the results of the Barnes maze test;

[0120] Figure 16 shows the results of liquid phase chip detection of Aβ protein in brain tissue of experimental animals, where A, Aβ 1-40 Detection results; B, Aβ 1-42 The test results;

[0121] FIG17 shows the results of immunohistochemical staining of pTau-181 in brain tissues of experimental animals, wherein A shows the detection results of pTau-181 in the cerebral cortex of mice; B shows the detection results of pTau-181 in the hippocampus of mice. DETAILED DESCRIPTION

[0122] The present application is further described below with reference to examples. It should be understood that the examples are only used to further illustrate and explain the present application and are not intended to limit the present application.

[0123] Unless otherwise defined, technical and scientific terms used in this specification have the same meaning as those commonly understood by those skilled in the art. Although methods and materials similar or identical to those described herein may be used in experiments or practical applications, the materials and methods are described herein below. In the event of a conflict, the present specification, including definitions, will prevail. In addition, the materials, methods, and examples are provided for illustrative purposes only and are not intended to be limiting. The present application is further described below with reference to specific examples, which are not intended to limit the scope of this application.

[0124] definition

[0125] GLP-1 receptor agonists

[0126] As used herein, the term "GLP-1 receptor agonist" refers to a compound that fully or partially activates the human GLP-1 receptor. A GLP-1 receptor agonist should exhibit "GLP-1 activity," which refers to the ability of the compound (i.e., a GLP-1 receptor agonist) to bind to the GLP-1 receptor and initiate a signal transduction pathway, thereby leading to an insulinotropic effect or other physiological effects known in the art.

[0127] In this application, the severity of dementia varies. In some embodiments, the term "dementia" as used herein refers to all forms and stages of the dementia disease continuum. In some embodiments, the dementia is selected from the indications defined in ICD-11: dementia due to Alzheimer's disease; dementia due to early-onset Alzheimer's disease; autosomal dominant Alzheimer's disease dementia, presenilin 1 mutation; autosomal dominant Alzheimer's disease dementia, presenilin 2 mutation; autosomal dominant Alzheimer's disease dementia, amyloid precursor protein mutation; dementia due to late-onset Alzheimer's disease; Alzheimer's disease dementia, mixed type, with cerebrovascular disease; Alzheimer's disease dementia, mixed type, with other non-vascular causes; non-amnestic Alzheimer's disease dementia subtype; non-amnestic Alzheimer's disease dementia, logopenic variant; non-amnestic Alzheimer's disease, logopenic variant, with primary progressive aphasia; nonamnestic Alzheimer's disease dementia, visuospatial variant; nonamnestic Alzheimer's disease dementia, visuospatial variant, with posterior cortical atrophy; nonamnestic Alzheimer's disease dementia, frontal variant; Alzheimer's disease dementia with psychosis; Alzheimer's disease dementia with depression; dementia due to cerebrovascular disease; hemorrhagic subtype of vascular dementia; ischemic subtype of vascular dementia; multi-infarct dementia; single critical infarct dementia; dementia due to subcortical vascular encephalopathy; dementia due to anoxic encephalopathy; dementia due to genetic causes; Dementia due to central nervous system vasculitis; Dementia due to hypertensive encephalopathy; Dementia due to intracerebral hypertensive hemorrhage; Dementia due to cerebral amyloid angiopathy; Dementia due to Lewy body disease; Frontotemporal dementia; Frontotemporal dementia, behavioral variant; Frontotemporal dementia, language variant; Frontotemporal dementia, nonfluent or agrammatic variant; Frontotemporal dementia, semantic variant; Frontotemporal dementia, logopenic variant; Frontotemporal dementia with motor neuron disease; Frontotemporal dementia with familial inclusion body myopathy and Paget's disease of bone; Frontotemporal dementia caused by inherited mutations; Frontotemporal dementia caused by C9orf72 mutations; Frontotemporal dementia caused by M Frontotemporal dementia caused by APT mutations; Frontotemporal dementia caused by VCP mutations; Frontotemporal dementia caused by GRN mutations; Frontotemporal dementia caused by CHMP2B mutations; Frontotemporal dementia caused by FUS mutations; Frontotemporal dementia caused by TARDBP mutations; Frontotemporal dementia caused by other mutations or novel mutations; Dementia caused by psychoactive substances, including drugs; Dementia caused by alcohol abuse; Dementia caused by use of sedatives, hypnotics, or anxiolytics; Post-hallucinogenic perceptual disorder; Dementia caused by use of volatile inhalants; Post-radiation dementia; Dementia caused by carbon monoxide poisoning; Dementia caused by drug poisoning; Dementia or Parkinson's disease caused by manganese poisoning;Dementia due to other classified disorders; dementia due to certain specific degenerative disorders of the central nervous system; dementia due to Parkinson's disease; dementia due to Huntington's disease; dementia due to corticobasal degeneration; dementia due to progressive supranuclear palsy; dementia due to neurofilament inclusion disease; dementia due to progressive subcortical gliosis; dementia due to multiple system atrophy; dementia due to spinocerebellar ataxia; dementia due to neurodegeneration with brain iron accumulation; dementia due to leukodystrophy; dementia due to Guam Parkinsonism-dementia syndrome; Dementia due to certain infectious diseases; dementia caused by human immunodeficiency virus; dementia due to neurosyphilis; dementia due to herpes encephalitis; dementia due to trypanosomiasis; dementia due to neurocysticercosis; dementia due to Lyme disease; dementia due to Whipple's disease; dementia due to progressive multifocal leukoencephalopathy; certain primary degenerative dementias; dementia with neurofibrillary tangles; familial multisystem tauopathy; argyrophilic grain disease; dementia due to certain central nervous system disorders; dementia due to multiple sclerosis; dementia due to prion diseases Dementia; Dementia due to sporadic Creutzfeldt-Jakob disease; Dementia due to variant Creutzfeldt-Jakob disease; Dementia due to familial Creutzfeldt-Jakob disease; Dementia due to iatrogenic Creutzfeldt-Jakob disease; Dementia due to sporadic fatal insomnia; Dementia due to fatal familial insomnia; Dementia due to Gerstmann-Straussler-Scheinker syndrome; Dementia due to Kuru; Dementia due to acute demyelinating encephalomyelitis; Dementia due to subacute sclerosing panencephalitis; Dementia due to Hashimoto's encephalopathy; Dementia due to paraneoplastic encephalitis Dementia caused by: Dementia caused by autoimmune encephalitis; Dementia caused by a primary central nervous system tumor; Dementia caused by a metastatic brain tumor; Dementia caused by epilepsy; Dementia caused by normal pressure hydrocephalus; Dementia caused by a metabolic disorder involving the brain; Dementia caused by head injury; Dementia caused by a chronic subdural hematoma; Dementia caused by obstructive hydrocephalus; Dementia caused by exposure to heavy metals and other toxins; Dementia caused by nutritional deficiencies; Dementia caused by thiamine deficiency; Dementia caused by vitamin B12 deficiency; Dementia caused by folic acid deficiency; Dementia caused by vitamin E deficiency Dementia caused by deficiency; dementia caused by iron deficiency; dementia caused by other nutritional deficiencies; dementia caused by pellagra; dementia caused by metabolic abnormalities; dementia caused by hypercalcemia; dementia caused by acquired hypothyroidism; dementia caused by Wilson's disease; dementia caused by dialysis; dementia caused by liver failure; dementia caused by renal failure; dementia caused by chromosomal abnormalities; dementia caused by Down syndrome; dementia caused by fragile X syndrome; dementia caused by rheumatic diseases; dementia caused by polyarteritis nodosa; dementia caused by systemic lupus erythematosus;Dementia caused by Behçet's disease; dementia caused by certain specific causes; behavioral or psychological disorders of dementia; psychotic symptoms of dementia; emotional symptoms of dementia; anxiety symptoms of dementia; apathy of dementia; agitation or aggression of dementia; disinhibition of dementia; wandering of dementia; terminal dementia; degenerative dementia; precocious psychotic disorder; delusional dementia; precocious dementia of unspecified type; senile dementia; and senile dementia. In some embodiments, dementia is selected from mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia, dementia with Lewy body disease, frontotemporal dementia, precocious dementia, and senile dementia. In some embodiments, dementia is Alzheimer's continuum with mild cognitive impairment or mild dementia. In some embodiments, dementia is mild cognitive impairment, such as mild cognitive impairment of the Alzheimer type. In some embodiments, the dementia is Alzheimer's disease, such as preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease, or prodromal Alzheimer's disease. In some embodiments, the dementia is mild cognitive impairment of the Alzheimer's type. In some embodiments, the dementia is mixed dementia. In some embodiments, the dementia is vascular dementia. In some embodiments, the dementia is dementia with Lewy bodies. In some embodiments, the dementia is frontotemporal dementia. In some embodiments, the dementia is presenile dementia. In some embodiments, the dementia is senile dementia.

[0128] As used herein, "neurodegenerative diseases or conditions" refer to diseases caused by the dysregulation or loss of neurons in the brain and / or spinal cord, which may manifest as motor dysfunction (such as cerebellar ataxia) and / or memory and related dysfunction. Neurodegenerative diseases can be caused by a variety of factors, including but not limited to:

[0129] Synaptic and / or synaptic function damage, decreased neurogenesis, neuronal apoptosis, oxidative stress damage, amyloid metabolic disorders, neurofibrillary tangles, activation of innate immune cells and / or neuroinflammation,

[0130] Preferably, the inducement is selected from: the influence of dopaminergic neuron loss induced by preformed fibrils of α-synuclein, the influence of β-amyloid (AmyloidβAβ) protein in neurons (such as Aβ 1-42 , Aβ 1-40 ) is abnormally elevated or forms amyloid plaques, toxic effects caused by abnormal elevation of Tau protein or phosphorylated Tau (pTau) protein in neurons or aggregation to form neurofibrillary tangles, and / or effects induced by elevation of glial fibrillary acidic protein (GFAP) (such as neuroinflammation, preferably neurogliosis).

[0131] The neurodegenerative diseases include, but are not limited to, dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis, etc.

[0132] Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. Unless the context indicates otherwise, all numerical values ​​provided herein are modified by the term "about".

[0133] "Ameliorate" means to reduce, inhibit, attenuate, weaken, arrest or stabilize the development or progression of a disease.

[0134] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional unrecited elements or method steps.

[0135] "Control" or "reference" refers to a standard of comparison. As used herein, a sample or subject that is "changed compared to a control" is understood to have a level that is statistically different from a sample from a normal, untreated or control sample. Control samples include, for example, cells in culture, one or more laboratory test animals, or one or more human subjects. Methods for selecting and testing control samples are within the capabilities of those skilled in the art. The analyte can be a naturally occurring substance (e.g., an antibody, a protein) characteristically expressed or produced by a cell or organism, or a substance (e.g., beta-galactosidase or luciferase) produced by a reporter gene construct. Depending on the method used to detect, the amount of change and the measured value can be different. Statistical significance is determined within the capabilities of those skilled in the art, for example, as the number of standard deviations from the mean value equivalent to a positive result.

[0136] The terms "effective amount" and "therapeutically effective amount" of a formulation or formulation component refer to a sufficient amount of a formulation or component, alone or in combination, to provide the desired effect. For example, an "effective amount" refers to the amount of a compound, alone or in combination, required to improve the symptoms of a disease (e.g., prostate cancer) relative to an untreated patient. The effective amount of the active compound used to implement the present invention for treating a disease varies depending on the mode of administration, age, weight, and general health of the subject. Ultimately, the attending physician or veterinarian will determine the appropriate amount and dosage regimen. This amount is referred to as an "effective" amount.

[0137] "Subject" refers to a mammal, including but not limited to a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. The subject is preferably a mammal in need of treatment, such as a subject that has been diagnosed with a disease or is susceptible to the disease. The mammal is any mammal, such as a human, a primate, a mouse, a rat, a dog, a cat, a horse, and livestock or animals raised for food consumption, such as cattle, sheep, pigs, chickens, and goats. In a preferred embodiment, the mammal is a human.

[0138] As used herein, the term "sample" refers to a biological sample obtained for in vitro evaluation. About methods disclosed herein, sample or patient sample preferably can include any body fluid or tissue. In certain embodiments, body fluid includes but is not limited to blood, plasma, serum, lymph, breast milk, saliva, mucus, semen, vaginal secretions, cell extracts, inflammatory effusions, cerebrospinal fluid, feces, vitreous humor or urine obtained from a subject. In some aspects, sample is a composite plate of at least two of a blood sample, a plasma sample, a serum sample and a urine sample. In exemplary aspects, sample includes blood or a portion thereof (for example, plasma, serum, the portion obtained via leukocyte apheresis). Preferred sample is whole blood, serum, plasma or urine. Sample can also be the partially purified part of a tissue or body fluid.

[0139] As used herein, the terms "treat," "treating," "treatment," and the like refer to administering an agent or formulation to a clinically symptomatic individual suffering from an adverse condition, disorder, or disease in order to achieve a reduction in the severity and / or frequency of the symptoms, eliminate the symptoms and / or their underlying causes, and / or promote improvement or remediation of the damage. It should be understood that, although not excluded, treating a disorder or condition does not require complete elimination of the disorder, condition, or symptoms associated therewith.

[0140] The terms "prevent," "preventing," "prevention," "prophylactic treatment," and the like refer to the administration of an agent or composition to an asymptomatic individual who is at risk for, susceptible to, or susceptible to a particular adverse condition, disorder, or disease, and thus involves preventing the occurrence of symptoms and / or their underlying causes.

[0141] In some cases, the composition of the present application is administered orally or systemically. Other modes of administration include rectal route, topical route, intraocular route, oral route, intravaginal route, intracisternal route, intraventricular route, intratracheal route, nasal route, transdermal route, intra-implant / on-implant route or parenteral route. The term "parenteral" includes subcutaneous, intrathecal, intravenous, intramuscular, intraperitoneal or infusion. Intravenous or intramuscular routes are not particularly suitable for long-term treatment and prevention. However, in emergency situations, they may be preferred. Compositions comprising the present invention can be added to physiological fluids, such as blood. Due to the convenience and dosage regimen for the patient, oral administration may be preferred for preventive treatment. Parenteral mode (subcutaneous or intravenous) may be preferred for the treatment of more acute diseases or for patients who cannot tolerate enteral administration due to gastrointestinal intolerance, intestinal obstruction or other critical illnesses. Inhalation therapy may be most suitable for pulmonary vascular disease (for example, pulmonary hypertension).

[0142] The pharmaceutical composition can be assembled into a kit or pharmaceutical system. The kit or pharmaceutical system according to this aspect of the present application includes a carrier device, such as a box, carton, or tube, which has one or more tightly confined container devices, such as a vial, tube, ampoule, bottle, syringe, or bag. The kit or pharmaceutical system of the present application may also include instructions for use of the kit.

[0143] The recitation of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable or aspect herein includes the embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0144] Any composition or method provided herein can be combined with one or more of any other compositions and methods provided herein.

[0145] Pharmaceutical composition

[0146] The GLP-1 receptor agonist can be administered in the form of a pharmaceutical composition, which can be in liquid or solid form.

[0147] The pharmaceutical compositions described herein may further comprise one or more pharmaceutically acceptable excipients, such as excipients selected from a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer, and a surfactant. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, such as one or more selected from a buffer, an isotonicity agent, and a preservative. The formulation of pharmaceutical active ingredients with various excipients is known in the art. The term "excipient" generally refers to any component other than an active therapeutic ingredient, such as a GLP-1 receptor agonist. An excipient may be an inert substance, an inactive substance, and / or a non-pharmaceutically active substance.

[0148] The pharmaceutical composition may be in the form of a solution or a suspension.

[0149] The solid composition can be a solid composition suitable for oral administration, as further described herein. In some embodiments, the solid composition comprises at least one pharmaceutically acceptable excipient. As used herein, the term "excipient" refers generally to any component other than an active therapeutic ingredient or active pharmaceutical ingredient (API). An excipient can be a pharmaceutically inert substance, an inactive substance, and / or a therapeutically or medically inactive substance.

[0150] The solid composition may further comprise a delivery agent or absorption enhancer, which, for the present invention, is an excipient capable of increasing oral exposure to the GLP-1 receptor agonist. The delivery agent may be a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (also referred to herein as a salt of NAC).

[0151] In some embodiments, the composition used in the present application is in the form of a solid composition for oral administration, such as a tablet. The solid composition contains a lubricant, such as magnesium stearate.

[0152] Oral administration: The GLP-1 receptor agonist can be administered orally, for example in the form of tablets, coated tablets, sachets, or capsules such as hard or soft gelatin capsules, and all such compositions are considered solid oral dosage forms. Oral administration can be once-daily administration. In some embodiments, the composition can be granulated before compression into a tablet. The composition may comprise a granular portion and / or an extragranular portion, wherein the granular portion has been granulated and the extragranular portion has been added after granulation. The GLP-1 receptor agonist may be contained in the granular portion or the extragranular portion. In some embodiments, the extragranular portion comprises the GLP-1 receptor agonist. In embodiments, the extragranular portion may further comprise a lubricant and / or a glidant. In embodiments, the granular portion may comprise a lubricant and / or a glidant. In embodiments, the granular portion and the extragranular portion comprise a lubricant and / or a glidant. Examples

[0153] 1 Experimental information

[0154] 1.1 Model establishment

[0155] In this study, male SPF-grade C57BL / 6J APP / PS1 mice (Beijing Huafukang Biotechnology Co., Ltd.), weighing 23.35-30.06 g, were used as a model mouse for Alzheimer's disease efficacy testing. These mice are derived from a cross between PrP-hAPPK595N / M596L dementia model mice and PrP-hPS1dE9 dementia model mice. Gene expression is stable, and cognitive and behavioral changes appear between 3 and 6 months of age. Senile plaques appear around 5 months of age, and extensive senile plaque formation occurs around 12 months of age. Negative littermates (hereinafter referred to as the normal control group) consisted of male SPF-grade C57BL / 6J mice (Beijing Huafukang Biotechnology Co., Ltd.). These mice share the same genetic background as APP / PS1 mice, exhibit strong resistance, stable genetic traits, and high exploratory potential. C57BL / 6J mice were used as controls for drug efficacy testing. Mice were quarantined before entry and, after an acclimatization period and no other health issues, were used in this experiment.

[0156] 1.2 Grouping Information

[0157] The experiment was divided into four groups: normal control group (WT), vehicle control group (Vehicle), donepezil hydrochloride positive control group (Donepezil), and ecnoglutide test group (Ecnoglutide); a semaglutide positive control group was also added in the supplementary experiment.

[0158] Based on the total distance traveled, animals with a range of ±50% close to the mean were randomly grouped. Mice with a range of distances from the mean or in poor condition due to injuries from fighting were not included in the experiment. A total of 17-19 animals were selected from each group for the experiment.

[0159] 1.3 Dosage Information

[0160] Route of administration: The WT group received subcutaneous (sc) injection of normal saline, and the Vehicle group received subcutaneous injection of ecnoglutide injection solvent (disodium hydrogen phosphate, propylene glycol, phenol, injection water); the Donepezil hydrochloride positive control group received oral gavage (ig) at a dose of 1.5 mg / kg; the ecnoglutide test group received subcutaneous injection at a dose of 0.015 mg / kg; the Semaglutide positive control group received subcutaneous injection at a dose of 0.05 mg / kg; the administration volume for all groups was 5 mL / kg.

[0161] Dosing frequency and cycle: The day of administration was defined as the first day of the experiment, recorded as D1, once / day (QD), for 7 consecutive months.

[0162] For specific dosing information, see 1.

[0163] Table 1 Dosage information

[0164] Ecnoglutide is N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

[0165] 1.4 Animal survival

[0166] Compared with WT mice, the APP / PS1 mouse model has a high natural mortality rate. The survival of animals was recorded every day after drug administration. During the drug administration period, there was no significant difference in the mortality of mice between the drug or vehicle control groups. The animal deaths in this experiment were all within the normal range.

[0167] 1.5 Main Experiments and Methods

[0168] Pathological examination

[0169] At the end of the experiment, all surviving animals were dissected and half of their brains were fixed with 4% paraformaldehyde to analyze the brain tissue amyloid plaques and Aβ 1-42 , Aβ 1-40 , GFAP, Tau and other markers. Unless otherwise specified in the experiment, the pH of PBS buffer was 7.4.

[0170] Immunohistochemistry

[0171] 1) Embedding: Fixed tissue samples were rinsed with running water for 30 min, then trimmed and placed in plastic pathology embedding baskets for dehydration (75% ethanol for 6 h, 85% ethanol for 10 h, 95% ethanol for 4 h, anhydrous ethanol I for 2 h, anhydrous ethanol II for 2 h), transparentized (xylene I for 20 min, xylene II for 15 min), immersed in wax for 3 h, and finally embedded in paraffin.

[0172] 2) Sectioning: Cut the tissue into 4 μm thick slices. Flatten the tissue in warm water, place it on a non-slip glass slide, and bake the slices at 60°C for at least 2 h.

[0173] 3) Staining: Paraffin sections were immersed in xylene for 10 minutes × 3 times, immersed in anhydrous ethanol for 3 minutes × 3 times, and then immersed in 95% and 75% ethanol, each for 3 minutes twice. Excess liquid was removed before each replacement of the immersion reagent. After rinsing with distilled water, the sections were placed in PBS buffer, and then antigen repair was performed using citric acid buffer (PH = 6.0). A commercial kit (Beijing Zhongshan Jinqiao, CAS No. / Cat. No.: SP9001) was used for further staining. 100 μL of endogenous peroxidase blocker was added, incubated at room temperature for 10 minutes, and rinsed with PBS buffer for 3 minutes × 3 times. 100 μL or an appropriate amount of normal goat serum working solution for blocking was added, incubated at room temperature for 10 to 15 minutes, and the serum was discarded. 100 μL of primary antibody (Aβ 1-40 : abcam, CAS number / product number: AB5074P, dilution ratio is 1:200; Aβ 1-42 : EMD Millipore Corporation, CAS No. / Cat. No. ab201061, dilution ratio 1:400), incubate at 4°C overnight, rewarm at 37°C for 1 hour, add 100 μL of biotinylated secondary antibody, incubate at room temperature for 15 minutes, add 100 μL of horseradish enzyme-conjugated streptavidin working solution, incubate at room temperature for 15 minutes, and rinse three times with PBS buffer for 3 minutes before adding new reagents. Add an appropriate amount of freshly prepared DAB color development solution (Zhongshan Jinqiao, CAS No. / Cat. No. ZLI-9019) and incubate at room temperature for 2 minutes. After rinsing, incubate with hematoxylin (Thermo Fisher, CAS No. / Cat. No. 7211) solution for 14 seconds, differentiate, rinse, and return to blue. Dehydrate, clear, and mount. Observe target expression under a microscope and photograph using a microscopy system.

[0174] Liquid chip detection

[0175] This liquid phase chip technology service uses the Merck Millipore liquid phase chip kit (kit catalog number: MHSTCMAG-70K) and is combined with the experimental detection content and performed according to the kit instructions. In summary, the sample to be tested is homogenized and mixed by vortexing, and ultrafiltration is concentrated; the standard, quality control (QC), and serum matrix in the kit are mixed; the magnetic beads are mixed after vortexing; the standard is prepared by gradient dilution, which is a 4-fold dilution; 200 μL of wash buffer is added to wash the plate, vortex for 10 minutes, remove the liquid, and spin dry; 50 μL of standard and quality control are added to the corresponding wells; 50 μL of the corresponding matrix solution (or tissue lysis buffer) is added to the background well; 25 μL of assay buffer is added to the corresponding well of the sample; 25 μL of sample is added to the sample well; 25 μL of mixed magnetic beads are added to each well; the plate is sealed and incubated overnight at 4°C in the dark with vortexing; the plate is washed three times using a magnetic plate washer, with 200 μL of wash buffer each time, and it needs to be left on the magnetic plate washer for 1 minute; 25 μL of detection antibody (GFAP: Cell Signaling) that has been restored to room temperature is added to each well Technology, CAS number / category number: 80788S, dilution ratio of 1:200), seal the plate, incubate with shaking at room temperature in the dark for 1 hour; add 25 μL of Streptavidin-Phycoerythrin restored to room temperature to each well, seal the plate, incubate with shaking at room temperature in the dark for 30 minutes; wash the plate three times using a magnetic plate washer with 200 μL of Wash Buffer each time, and let it stand on the magnetic bead plate washer for 1 minute; add 150 μL of plate reader sheath fluid, seal the plate, and resuspend with shaking at room temperature in the dark for 5 minutes; read the plate with a MAGPIX instrument, export the data, and analyze the results.

[0176] ELISA test

[0177] The assays were performed using commercial kits (brain Tau protein: sabbiotech, CAS No. / Cat. No. EK5154; brain pTau-181: raybiotech, CAS No. / Cat. No. EK5154PEL-Tau-T181-Q) according to the assay specifications. In summary, standard solutions ranging from 72 to 0.1 pM were prepared at room temperature in a three-fold concentration gradient. Well strips were labeled according to the assay, and 100 μL of the corresponding standard or mouse brain homogenate sample was added to each well, gently rocking overnight at 4°C. 100 μL / well of 1× biotinylated anti-phospho-Tau (Thr181) or anti-Tau antibody was added at a dilution of 1:200 and incubated for 1 hour. 100 μL of HRP was added to each well, and the wells were incubated at room temperature for 1 hour with gentle rocking. Before each incubation with new reagents, 300 μL of 1× wash buffer was added to each well, and the wells were washed four times before removing the remaining solution. Add 100 μL of TMB to each well and incubate with gentle shaking at room temperature for 30 minutes in the dark. Add 50 μL of stop solution to each well and read immediately at 450 nm. Calculate sample concentrations by creating a standard concentration curve.

[0178] 1.5.2 Morris Water Maze

[0179] The day before the experiment, mice were placed in a maze room for acclimatization. A suitable circular water maze was used, with spatial orientation markers placed around the maze where the animals could see it. Water was placed in the maze room before the experiment, and the temperature was controlled at 19-22°C. The experiment consisted of two phases: a training phase and a testing phase. The experimental data was recorded using a camera and software (such as TopScan) for analysis.

[0180] 1) Training period: A small white pool platform with a diameter of 8 cm is placed 1-2 cm below the water surface. The animal is placed in the water with its head facing the pool wall. The placement position is randomly selected from the starting positions of the four quadrants. The time (seconds, s) from the time the animal is placed in the water to the time it finds the underwater platform is recorded. In the first few training sessions, if the time to find the underwater platform exceeds 60 seconds, guide the animal to the platform (try not to touch the animal's limbs with your hands or the guiding tools with the animal's limbs during the guidance process). After the animal stays on the platform for more than 6 seconds, remove the animal, wipe it dry, and place it on a heating pad for 5 minutes, dry it, and then put it back in the cage. Each animal is trained at least twice a day. The number of training sessions can be increased or decreased according to the experimental needs and the number of animals. Training should be continued for 5 days.

[0181] 2) Testing Phase: Spatial Probe Test: After the final acquisition training session, the platform was removed on the second day, and the animal was placed in the water in the quadrant opposite the original platform. The time it took for the animal to first contact the platform within 60 seconds and the number of platform crossings were recorded.

[0182] 1.5.3 Active Avoidance

[0183] A 30 × 30 × 20 cm white-bottomed box was divided evenly into a light chamber and a dark chamber, connected by a restricted opening. Each chamber was equipped with an infrared camera. The dark chamber was equipped with a metal grid floor capable of being charged, and the light chamber was equipped with a 200-400 lux light source. The experimental animals were placed in the behavioral testing room one day in advance for 24 hours of acclimatization. The experimental period was divided into two phases: training and testing. The experimental data were recorded using a camera and software (such as TopScan) for analysis.

[0184] During the training phase, the animal was placed in the middle of a dark box and allowed to explore for 10 seconds before recording began. After 10 seconds, the barrier between the boxes was removed and a 0.5 mA electric shock was administered for 2 seconds, with a 6-second interval between each shock. The shock was stopped after the animal voluntarily left the dark box and entered the light box through the middle door to escape the shock. The animal was allowed to remain in the dark box for 10 seconds before being returned to its cage.

[0185] Testing period: 24 hours after training, place the animal in the middle of the light box and allow it to explore for 10 seconds. Immediately begin recording. After 10 seconds of video recording, remove the barrier between the boxes and record the animal's free movement for 5 minutes.

[0186] The latency period of escaping from the dark box, the number of escape failures, and the total activity time and distance of the light box and dark box of each group of mice during the training and testing periods were recorded and analyzed.

[0187] 1.5.4 Nesting experiment

[0188] All nesting animals were housed in individual cages and given at least 24 hours to acclimate. Before dark, a nesting material, made of paper towels folded into a block approximately 0.5 cm thick, was placed in the middle of the cage. After 12 hours, the nests were evaluated based on the shape of the nests and the degree of tearing of the paper towels. The nests were generally evaluated on a 5-point scale:

[0189] Score 1: Nesting material is largely intact (>90% intact). Score 2: Nesting material is concentrated in one corner of the cage with no nest shape and is partially torn (50-90% still intact). Score 3: No nest shape, but the nesting material is mostly torn (<50% of the nesting material is intact, but <90% is within one-quarter of the cage floor area, i.e., the cotton is not concentrated in the nest, but is scattered around the cage. Note: Material may sometimes be in a generalized nest area, but the key definition is that 50-90% has been torn), or the nesting material is concentrated in one corner of the cage with the shape of a nest. Score 4: Nesting material is concentrated in one corner of the cage with a nest shape or when >90% of the nesting material is torn but there is no nest shape, a score of 4 is also given. Score 5: A nearly perfect nest or >90% of the nesting material is torn.

[0190] 1.5.5 Open field test

[0191] The experimental animal was gently removed from its home cage, facing away from the experimenter, and placed in the center of a 50 cm blue PVC cube-shaped open-field box. The open-field box was divided into 16 equal 4×4 grids, with the center 4 grids forming the central area. A camera mounted directly above the open-field box recorded each animal's movements for approximately 10 minutes. The movement trajectories of all animals were recorded using TOPSCAN software (Cleversys, USA). The distance traveled, the duration spent in the central area, the corners, and the entire open-field box, as well as the number of entries and average speed, were analyzed.

[0192] 1.5.6 Weight

[0193] The body weight of the surviving animals in each group was measured regularly, once a week during the adaptation period, once before grouping, and once a week during the drug administration period.

[0194] 1.5.7 Barnes maze test

[0195] The maze consisted of a circular, black, medical-grade PVC platform, 80 cm in diameter and 100 cm in height. The platform had 18 inaccessible, 5 cm-diameter holes evenly distributed around the perimeter. Only one of the holes was connected to a hidden box for the mice to hide in. Spatial orientation markers were placed around the maze within sight of the animals. The day before the experiment, the animals were individually placed in the hidden box from the target hole for 5 minutes. At the start of the experiment, the mice were restrained for 5 seconds in the start box in the center of the maze. A 200-400 lux light source was illuminated on the platform to stimulate avoidance. The start box was then removed, and the animals were recorded using a camera and software (e.g., TopScan) for analysis. Over five days of training, the animals learned to memorize the location of the target box. After each training session, the platform was cleaned with 70% alcohol, and the correct hole was replaced, but the spatial location of the hole remained unchanged. On the sixth day, the target box was removed, and learning and memory abilities were assessed by recording and analyzing parameters such as the latency of the mice to reach the target box.

[0196] 1.6 Statistical analysis

[0197] The experimental data were statistically analyzed using EXCEL and IBM SPSS Statistics 22.0.

[0198] All measured data are expressed as mean ± SD. Graph Pad Prism 8 software was used to plot parameters before and after administration of the drug in different groups. Data were analyzed using SPSS 22.0 statistical software. Homogeneity of variance was tested using the Levene test. When homogeneity of variance was found (P ≥ 0.05), inter-group differences were compared using the Dunnett's LSD method within one-way analysis of variance (ANOVA). When heterogeneity of variance was found (P < 0.05), inter-group differences were compared using the Mann-Whitney U test (MW method) within the Kruskal-Wallis H rank sum test (KW method). Animal survival was compared between groups using the log-rank test within the product limit method (KM method).

[0199] 2. Experimental Results

[0200] 2.1 Morris water maze

[0201] The Morris water maze mainly tests the spatial memory and reference memory of animals. Since the spatial and reference memory of the Morris water maze in mice are long-term memories, continuous water maze tests may interfere with the results. Therefore, in the entire experiment, only two water maze tests were set up, one before drug administration and the other 6 months after drug administration. The water maze experiment is divided into two stages: directional navigation (training period) and spatial exploration (testing period). The main detection indicator of directional navigation is the latency of mice to find the hidden underwater platform. By comparing the latency of multiple training days, the learning process of animals is reflected. The main detection indicators of the spatial exploration experiment are the number of ring crossings, the latency of exploring the target area, and the percentage of time spent in the target quadrant, which reflect the results of memory.

[0202] Before dosing, all animals were tested in a water maze (WT, n=17; APP / PS1, n=51). During the training phase, APP / PS1 mice had a significantly longer latency to find the platform than WT mice (P<0.001, Figure 1A), indicating memory impairment in APP / PS1 mice. Furthermore, the average swimming speed of APP / PS1 mice during the training phase was significantly faster than that of WT mice (P<0.001, Figure 1B), reflecting their anxiety. During the test phase, APP / PS1 mice found the platform significantly less frequently and spent significantly less time in the target quadrant than WT mice (P<0.001, Figure 1C, Figure 1E). The latency to find the target area was significantly higher in APP / PS1 mice than in WT mice (P<0.001, Figure 1D). Data are shown in Tables 2 and 3.

[0203] Table 2 Results of water maze training period before drug administration

[0204] Table 3 Results of the water maze test period before drug administration

[0205] Six months after dosing, all animals were tested again in the water maze. The data are shown in Table 4. Repeated measures analysis of latency and swimming speed during the five-day training period showed that the latency to find the platform in the Vehicle group was significantly higher than that in the WT group (P < 0.001, Figure 2A). The positive drug group, Donepezil, was able to find the platform faster than the Vehicle group (P = 0.043, Figure 2A). The ecnoglutide group had a significantly shorter latency to find the platform than the Vehicle group (P = 0.002, Figure 2A). During the training period, the swimming speed of the Vehicle group was significantly higher than that of the WT group (P < 0.001, Figure 2B), while the swimming speed of the ecnoglutide group was significantly lower than that of the Vehicle group (P = 0.032, Figure 2B).

[0206] A one-way ANOVA was performed on the number of times the animals found the platform, the latency to find the platform, and the time the animals spent in the target quadrant during the test period. Compared with the WT group, the Vehicle group found the platform significantly less often (P = 0.001, Figure 2C), the latency was significantly increased (P < 0.001, Figure 2D), and the time spent in the target quadrant was significantly reduced (P = 0.001, Figure 2E). All indicators showed obvious memory impairment. Compared with the Vehicle group, both the positive drug and the test product Ecnoglutide groups showed an effect on improving APP / PS1 memory impairment after administration.

[0207] Table 4 Results of water maze training period after 6 months of drug administration

[0208] 2.2 Active avoidance experiment

[0209] The active avoidance experiment utilizes the rodents' tendency to move toward darkness and avoid light. The animals are placed in a dark box and given a single foot shock from the dark box during training. The animals enter the light box through the middle door to escape the shock, allowing the animals to establish a fear memory of the aversive stimulus. After 24 hours, the animals are returned to the dark box, and the latency period for the animals to escape the dark box and enter the light box is recorded to test the animals' memory ability.

[0210] As shown in Figure 3 and Table 5, a one-way ANOVA analysis of the latency of the animals to escape from the dark box and enter the light box during the test period showed that the escape latency of the vehicle group was prolonged compared with the WT group (P<0.001). The escape latency of the positive drug group Donepezil was significantly shortened compared with the vehicle group (P=0.010). The escape latency of the ecnoglutide test group was significantly shortened compared with the vehicle group (P=0.014), all of which showed biological statistical differences. The data from the active avoidance test showed that the ecnoglutide test group could improve the memory impairment of APP / PS1 mice.

[0211] Table 5 Results of active avoidance experiment after 7 months of drug administration

[0212] 2.3 Nesting experiment

[0213] Nesting is a common daily behavior in mice. It is a maternal behavior that protects pups, an instinctive behavior for maintaining body temperature, and a behavioral mechanism for executive function and social interaction. Nesting behavior experimental research methods can reflect the social behavior and daily activities of mice. This experiment statistically analyzed and evaluated the nesting behavior of mice in the WT group, APP / PS1 group, and each treatment group before and after drug administration.

[0214] As shown in Figure 4 and Table 6, the nesting score of mice in the APP / PS1 group was lower than that of the WT group before dosing. Six months after dosing, the nesting score of the Vehicle group was consistent with that of the APP / PS1 group before dosing and was significantly lower than that of the WT control group (P=0.033). The nesting score of the ecnoglutide test group was significantly higher than that of the Vehicle group (P=0.038).

[0215] Table 6 Nesting experiment results

[0216] 2.4 Open field experiment

[0217] The open field test is primarily used to observe the animals' autonomous locomotion, exploratory behavior in novel environments, and emotional changes such as tension, anxiety, and depression. Generally, compared with the WT group, the APP / PS1 group showed a greater total distance traveled (P = 0.007, Figure 5A) and a greater number of center crossings (P = 0.003, Figure 5B).

[0218] As shown in Figure 6 and Table 7, after 3 months of administration, the total movement distance and the number of center crossings of the animals in the Vehicle group were significantly higher than those in the WT group (Figure 6A, P=0.005; Figure 6B, P=0.046), while the total movement distance and the number of center crossings of the animals in the group given the ecnoglutide test product were significantly lower than those in the Vehicle group (P=0.002, Figure 6A, P=0.005, Figure 6B), indicating that the test product improved the animals' autonomous movement ability, exploratory behavior in new and different environments, and emotions such as tension, anxiety and depression.

[0219] Table 7 Results of open field after 3 months of drug administration

[0220] 2.5 Immunohistochemical detection of amyloid plaques

[0221] Amyloid plaques are considered a key factor in Alzheimer's disease. In healthy neurons, amyloid precursor proteins, which have three domains (intracellular, intracellular and extracellular), are digested by alpha and gamma secretases. This digestion reaction produces some soluble polypeptides that can be broken down and recycled in the cell. However, when beta secretase combines with gamma secretase, insoluble beta amyloid peptides are produced. When beta amyloid peptides aggregate together, they form beta amyloid plaques that are harmful to cells. Beta amyloid plaques damage surrounding neurons by disrupting signaling between healthy neurons and by initiating an immune response that causes inflammation. These problems lead to severe damage to the brain and loss of some functions, such as memory and learning, and the clearance of amyloid plaques can help improve cognitive function.

[0222] After the administration of each group was completed, immunohistochemical staining was performed on the hemisphere sections of the animals to detect the area of ​​plaques. As shown in Figures 7A to C, Figures 8A to C, and Table 8, the amyloid plaques and Aβ in the Vehicle group were significantly higher than those in the WT group. 1-40 , Aβ 1-42 The positive areas of the Ecnoglutide group were significantly increased (P < 0.001, P = 0.003, P < 0.001), while the amyloid plaques and Aβ 1-40 Plaques, Aβ 1-42 The plaques were significantly reduced compared with the Vehicle group (P=0.020, P=0.034, P=0.034).

[0223] Table 8 Calculation results of amyloid plaque area

[0224] 2.6 Tau protein ELISA detection in brain tissue

[0225] Tau is a microtubule-associated protein that is highly expressed in the brain and serves as a structural element in the axonal cytoskeleton. In patients with Alzheimer's disease, pathological conditions such as chronic traumatic encephalopathy or other tauopathies can lead to phosphorylation of the Tau protein, which aggregates to form neurofibrillary tangles, leading to cognitive impairment. Elevated Tau and p-Tau levels in the brain are hallmarks of AD. As shown in Figure 9 and Table 9, the Tau concentration in the Vehicle group was higher than that in the WT group. After administration of ecnoglutide injection, the concentration in the ecnoglutide test group was significantly lower than that in the Vehicle group (P = 0.003).

[0226] Table 9 Tau protein ELISA test results

[0227] 2.7 Liquid-phase microarray detection of Aβ protein in brain tissue

[0228] Extracellular senile plaques formed by the deposition of Aβ peptides are a specific hallmark of AD. Abnormal Aβ accumulation in the brain can lead to neurodegeneration, neuroinflammation, impaired neuronal function, and ultimately cognitive decline. This process is mainly due to excessive Aβ production and Aβ clearance dysfunction caused by APP and PS1 / 2 gene mutations in familial AD. Therefore, improving Aβ clearance has become a promising therapeutic strategy for AD. In addition to relying on the above-mentioned immunohistochemistry, Aβ detection can also be performed by liquid phase chip or ELISA to detect Aβ in mouse brain tissue. 1-40 , Aβ 1-42 The protein concentration is determined by immunohistochemical plaque detection, which focuses on "localization" and is a semi-quantitative result; while liquid microarray detection focuses on "quantification" and is more accurate for detecting Aβ content.

[0229] The results are shown in Figure 10 and Table 10. 1-40 , Aβ 1-42 The concentration was significantly higher than that of the WT group. After 7 months of administration, the Aβ level in the brain tissue of the Ecnoglutide test group was significantly higher than that of the WT group. 1-40 , Aβ 1-42 The concentration was significantly lower than that in the Vehicle group.

[0230] Table 10 Aβ 1-40 , Aβ 1-42 Liquid chip test results

[0231] 2.8 GFAP immunohistochemical staining of brain tissue

[0232] AD pathology is associated with the morphological, molecular, and functional remodeling of astrocytes, a process known as reactive astrogliosis. Glial fibrillary acidic protein (GFAP), an intermediate filament structural protein, serves as a biomarker for reactive astrogliosis and is found at elevated levels in the blood of clinical AD patients.

[0233] GFAP immunohistochemistry results showed that in the mouse cortex and hippocampus, the Vehicle group showed significantly higher GFAP positive expression than the WT group, with the highest expression. However, GFAP expression in the ecnoglutide group was improved, remaining lower than that in the Vehicle group, indicating that ecnoglutide significantly reduces astrocyte activation. Representative GFAP staining images for each group are shown in Figures 11, 12, and 13, and the data are shown in Table 11.

[0234] Table 11 Quantification results of GFAP immunohistochemistry in cortex and hippocampus

[0235] 2.9 Animal weight changes

[0236] Because the test product is a GLP-1 peptide analogue with the effect of reducing body weight, the weight changes of the animals in each group were monitored during the experiment. The results, as shown in Figure 14, showed no significant difference in body weight between the vehicle control group and the WT control group. Compared with the vehicle group, the body weight and general condition of the surviving animals in each drug-treated group also showed no significant abnormalities.

[0237] 3. Comparative study of the effects of ecnoglutide and semaglutide

[0238] To further evaluate the efficacy of the ecnoglutide test product, the Semaglutide positive control group and the ecnoglutide test product group (Ecnoglutide) were evaluated in the Barnes maze test, brain tissue Aβ protein liquid phase chip detection and brain tissue pTau-181 immunohistochemical staining detection, respectively. A one-way analysis of variance was performed on each experimental group. The ecnoglutide test product group was administered subcutaneously at a dose of 0.015 mg / kg; the Semaglutide positive control group was administered subcutaneously at a dose of 0.05 mg / kg. The administration volume for all groups was 5 mL / kg.

[0239] In each experiment, APP / PS1 mice in the vehicle group exhibited abnormal behaviors or pathological features of neurodegeneration or Alzheimer's disease that were different from those in the wild-type C57BL / 6J group compared to the wild-type WT control group. Furthermore, ecnoglutide treatment improved these abnormal behaviors or pathological features in APP / PS1 mice. Furthermore, the improvement effects of the ecnoglutide and semaglutide treatment groups were compared, and the results are summarized in Figures 15-17.

[0240] In the Barnes maze test shown in Figure 15, the latency of mice in the Ecnoglutide-treated group was significantly shorter than that in the Semaglutide-treated group. In the liquid phase chip detection of Aβ protein in brain tissue shown in Figure 16, the Aβ protein in the brain of mice in the Ecnoglutide-treated group was significantly shorter than that in the Semaglutide-treated group. 1-40 and Aβ 1-42 Protein levels were lower. In the pTau-181 immunohistochemical staining assay shown in Figure 17, the pTau-181 levels in the cerebral cortex and hippocampus of mice treated with ecnoglutide were lower than those in the semaglutide-treated group. This shows that compared to the semaglutide-treated group, ecnoglutide has a better effect on improving cognitive, motor, memory behaviors and pathological states related to neurodegeneration and / or Alzheimer's disease.

[0241] Although the present invention has been disclosed above with reference to the embodiments, they are not intended to limit the present invention. Anyone with ordinary knowledge in the art may make slight changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be determined by the scope of the patent application attached hereto.

Claims

1. A method for treating a neurodegenerative disease or disorder, comprising administering a GLP-1 receptor agonist or a composition thereof to a subject in need thereof; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis or neurogliosis; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia or neurogliosis.

2. The method of claim 1, wherein the neurodegenerative disease is Parkinson's disease.

3. The method of claim 1, wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

4. The method according to claim 1 or claim 3, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ. 5 . The method according to claim 1 , comprising administering to a subject in need thereof an effective amount of a GLP-1 receptor agonist or a composition thereof to block or reduce the activation of resident innate immune cells.

6. The method according to any one of claims 1 to 5, comprising inhibiting the activation of immune cells by abnormally aggregated proteins by using a GLP-1 receptor agonist or a combination thereof.

7. The method according to any one of claims 1 to 6, wherein the amount of the GLP-1 receptor agonist or the composition thereof can effectively inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

8. The method according to any one of claims 1 to 7, wherein the innate immune cells are microglia and / or astrocytes. 9 . The method according to claim 1 , wherein the abnormally aggregated protein is Aβ protein or Tau protein.

10. The method according to any one of claims 1 to 9, wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog, or a derivative thereof, preferably a GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

11. The method according to any one of claims 1 to 10, wherein the GLP-1 receptor agonist or a composition thereof is administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intraosseously, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, and subcutaneously.

12. The method according to any one of claims 1 to 11, wherein the GLP-1 polypeptide analog derivative or composition thereof is administered subcutaneously; preferably, in the form of a solution or suspension, and optionally in the form of a solution comprising at least 90% water and having a pH in the range of 7.0-9.

0.

13. The method according to any one of claims 1 to 12, wherein the GLP-1 receptor agonist or a composition thereof is administered in a form selected from the group consisting of pills, capsules, tablets, granules, powders, salts, crystals, liquids, slurries, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

14. The method according to any one of claims 1 to 11 or claim 13, wherein the GLP-1 receptor agonist or a composition thereof is administered orally, preferably in the form of a tablet.

15. The method according to any one of claims 1 to 11 or claims 13-14, wherein the GLP-1 receptor agonist or a composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt such as NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I): Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II): 16 . The method according to claim 1 , wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 15 times per month.

17. The method according to any one of claims 1 to 16, wherein the GLP-1 receptor agonist or the composition thereof is administered once a week.

18. The method according to any one of claims 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 6 times per year.

19. The method according to any one of claims 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered once a month.

20. The method according to any one of claims 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered once every two months.

21. The method according to any one of claims 1 to 15, wherein the GLP-1 receptor agonist or the composition thereof is administered 1 to 2 times per day.

22. The method according to any one of claims 1 to 21, wherein the GLP-1 receptor agonist or the composition thereof has an in vivo half-life of 12 to 200 hours in non-human primates or humans.

23. The method according to any one of claims 1 to 22, wherein the GLP-1 receptor agonist or the composition thereof is administered at a dosage of 0.001 mg / kg / subject to 100 mg / kg / subject; or a single dose of a drug comprising a GLP-1 receptor agonist or the composition thereof can be provided to a subject at 0.001 mg / kg to 100 mg / kg.

24. The method according to any one of claims 1 to 23, wherein the GLP-1 receptor agonist or the composition thereof is administered at a dosage of 0.001 mg / kg / subject to 10 mg / kg / subject; or a single dose of a drug comprising a GLP-1 receptor agonist or the composition thereof can be provided to a subject at 0.001 mg / kg to 10 mg / kg.

25. The method according to any one of claims 1 to 24, wherein the GLP-1 receptor agonist or a composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

26. The method according to any one of claims 1 to 25, wherein the GLP-1 receptor agonist or a composition thereof can protect a subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

27. The method according to any one of claims 1 to 26, wherein the GLP-1 receptor agonist or a composition thereof can protect the subject from the effects induced by the increase of Aβ protein and / or Tau protein in neurons.

28. The method according to any one of claims 1 to 27, wherein the GLP-1 receptor agonist or composition thereof protects the subject from the effects induced by an increase in GFAP.

29. The method of any one of claims 1 to 28, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

30. The method of any one of claims 1 to 29, wherein in the subject relative to a control, synapses and / or synaptic function are preserved, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced, and chronic inflammatory responses are prevented.

31. The method according to any one of claims 1 to 30, wherein: The GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

32. Use of a pharmaceutically effective amount of a GLP-1 receptor agonist or a composition thereof in the preparation of a medicament for treating a neurodegenerative disease or condition; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis or neurogliosis; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia or neurogliosis.

33. The use according to claim 32, wherein the neurodegenerative disease is Parkinson's disease.

34. Use according to claim 32, wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

35. The use according to claim 32 or claim 34, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ.

36. The use according to any one of claims 32 to 35, comprising administering an effective amount of a GLP-1 receptor agonist or a composition thereof to a subject in need thereof to block or reduce the activation of resident innate immune cells.

37. The use according to any one of claims 32 to 36, comprising inhibiting the activation of immune cells by abnormally aggregated proteins by using a GLP-1 receptor agonist or a combination thereof.

38. The use according to any one of claims 32 to 37, wherein the amount of the GLP-1 receptor agonist or the composition thereof can effectively inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

39. The use according to any one of claims 32 to 38, wherein the innate immune cells are microglia and / or astrocytes.

40. The use according to any one of claims 32 to 39, The abnormally aggregated protein is Aβ protein or Tau protein.

41. The use according to any one of claims 32 to 40, wherein the GLP-1 receptor agonist or its composition comprises wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog or a derivative thereof, preferably the GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

42. The use according to any one of claims 32 to 41, wherein the GLP-1 receptor agonist or a composition thereof is administered orally, intravenously, topically, parenterally, intraperitoneally, intramuscularly, intrathecally, intralesionally, intracranially, intranasally, intraocularly, intracardially, intravitreally, intrabonely, intracerebrally, intraarterially, intraarticularly, intradermally, transdermally, transmucosally, sublingually, enterally, sublabially, by insufflation, by suppository, by inhalation, and subcutaneously.

43. The use according to any one of claims 32 to 42, wherein the GLP-1 polypeptide analog derivative or a composition thereof is administered subcutaneously; preferably, it is administered in the form of a solution or a suspension, and optionally administered in the form of a solution containing at least 90% water and having a pH in the range of 7.0-9.

0.

44. The use according to any one of claims 32 to 43, wherein the GLP-1 receptor agonist or a composition thereof is administered in a form selected from the group consisting of pills, capsules, tablets, granules, powders, salts, crystals, liquids, slurries, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

45. The use according to any one of claims 32 to 42 or claim 44, wherein the GLP-1 receptor agonist or the composition thereof is administered orally, preferably in the form of a tablet.

46. ​​The use according to any one of claims 32 to 42 or claims 44 to 45, wherein the GLP-1 receptor agonist or a composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt such as NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I): Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II):

47. The use according to any one of claims 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 15 times per month.

48. The use according to any one of claims 32 to 47, wherein the GLP-1 receptor agonist or the composition thereof is administered once a week.

49. The use according to any one of claims 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 2 to 6 times per year.

50. The use according to any one of claims 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered once a month.

51. The use according to any one of claims 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered once every two months.

52. The use according to any one of claims 32 to 46, wherein the GLP-1 receptor agonist or the composition thereof is administered 1 to 2 times a day.

53. The use according to any one of claims 32 to 52, wherein the GLP-1 receptor agonist or the composition thereof has an in vivo half-life of 12 to 200 hours in non-human primates or humans.

54. The use according to any one of claims 32 to 53, wherein the dosage of the GLP-1 receptor agonist or the composition thereof is 0.001 mg / kg / subject-100 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or the composition thereof can be provided to the subject at 0.001 mg / kg-100 mg / kg.

55. The use according to any one of claims 32 to 54, wherein the dosage of the GLP-1 receptor agonist or the composition thereof is 0.001 mg / kg / subject-10 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or the composition thereof can be provided to the subject at 0.001 mg / kg-10 mg / kg.

56. The use according to any one of claims 32 to 55, wherein the GLP-1 receptor agonist or a composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

57. The use according to any one of claims 32 to 56, wherein the GLP-1 receptor agonist or a composition thereof can protect a subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

58. The use according to any one of claims 32 to 57, wherein the GLP-1 receptor agonist or a composition thereof can protect a subject from the effects induced by the increase of Aβ protein and / or Tau protein in neurons.

59. The use according to any one of claims 32 to 58, wherein the GLP-1 receptor agonist or the composition thereof can protect the subject from the effects induced by the increase of GFAP.

60. The use according to any one of claims 32 to 59, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

61. The use according to any one of claims 32 to 60, wherein relative to a control, in the subject, synapses and / or synaptic function are protected, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced and chronic inflammatory responses are prevented.

62. The use according to any one of claims 32 to 61, wherein: The GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

63. A pharmaceutically effective amount of a GLP-1 receptor agonist or a composition thereof for treating a neurodegenerative disease or disorder; preferably, the neurodegenerative disease is selected from dementia, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia gravis or neurogliosis; preferably, the neurodegenerative disease is selected from Parkinson's disease, dementia or neurogliosis.

64. The GLP-1 receptor agonist or composition thereof according to claim 63, wherein the neurodegenerative disease is Parkinson's disease.

65. The GLP-1 receptor agonist or composition thereof according to claim 63, wherein the neurodegenerative disease is dementia; preferably, wherein the dementia is all forms and all stages of dementia.

66. A GLP-1 receptor agonist or composition thereof according to claim 63 or claim 65, wherein the dementia is mild cognitive impairment or Alzheimer's disease; preferably, wherein the dementia is selected from preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease and prodromal Alzheimer's disease, preferably Alzheimer's disease is Alzheimer's disease associated with the deposition of Aβ.

67. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 66, comprising administering an effective amount of the GLP-1 receptor agonist or composition thereof to a subject in need thereof to block or reduce the activation of resident innate immune cells.

68. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 67, wherein the GLP-1 receptor agonist or composition thereof inhibits activation of immune cells by abnormally aggregated proteins.

69. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 68, wherein the amount of the GLP-1 receptor agonist or composition thereof can effectively inhibit the secretion of inflammatory and / or neurotoxic mediators secreted by the activated innate immune cells.

70. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 69, wherein the innate immune cells are microglia and / or astrocytes.

71. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 70, wherein the abnormally aggregated protein is Aβ protein or Tau protein.

72. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 71, wherein the GLP-1 receptor agonist or composition thereof comprises wherein the GLP-1 receptor agonist comprises a GLP-1 polypeptide, a GLP-1 polypeptide analog, a PEGylated GLP-1 polypeptide analog, an Fc-fused GLP-1 polypeptide analog, an albumin-fused GLP-1 polypeptide analog or a derivative thereof, preferably the GLP-1 receptor agonist comprises Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37) polypeptide molecule.

73. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 72, wherein the GLP-1 receptor agonist or composition thereof is administered via oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhalation administration and subcutaneous administration.

74. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 73, wherein the GLP-1 polypeptide analog derivative or composition thereof is administered subcutaneously; preferably, in the form of a solution or suspension, and optionally in the form of a solution comprising at least 90% water and having a pH in the range of 7.0-9.

0.

75. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 74, wherein the GLP-1 receptor agonist or composition thereof is administered in a form selected from one of the following: pills, capsules, tablets, granules, powders, salts, crystals, liquids, slurries, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

76. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 75, wherein the GLP-1 receptor agonist or composition thereof is administered orally, preferably in the form of a tablet.

77. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 73 or claims 75 to 76, wherein the GLP-1 receptor agonist or composition thereof is administered in the form of a tablet comprising at least 20% (w / w), preferably at least 30% (w / w) of N-(8-(2-hydroxybenzoyl)amino)caprylic acid salt such as NAC salt; preferably, the NAC salt comprises the structural formula shown in formula (I): Further preferably, the NAC salt is PNAC, and the structural formula of the PNAC is shown in formula (II):

78. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered 2 to 15 times per month.

79. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 78, wherein the GLP-1 receptor agonist or composition thereof is administered once a week.

80. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 77, wherein the administration frequency of the GLP-1 receptor agonist or composition thereof is 2 to 6 times per year.

81. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered once a month.

82. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered once every two months.

83. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 77, wherein the GLP-1 receptor agonist or composition thereof is administered 1 to 2 times per day.

84. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 83, wherein the GLP-1 receptor agonist or composition thereof has an in vivo half-life of 12 to 200 hours in non-human primates or humans.

85. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 84, wherein the dosage of the GLP-1 receptor agonist or composition thereof is 0.001 mg / kg / subject-100 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or composition thereof can be provided to the subject at 0.001 mg / kg-100 mg / kg.

86. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 85, wherein the dosage of the GLP-1 receptor agonist or composition thereof is 0.001 mg / kg / subject-10 mg / kg / subject; or a single dose of the drug containing the GLP-1 receptor agonist or composition thereof can be provided to the subject at 0.001 mg / kg-10 mg / kg.

87. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 86, wherein the GLP-1 receptor agonist or composition thereof is provided to the subject for at least 1 month; preferably, the treatment lasts for at least 3 months.

88. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 87, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects of dopaminergic neuron loss induced by preformed α-synuclein fibrils.

89. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 88, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects induced by increased Aβ protein and / or Tau protein in neurons.

90. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 89, wherein the GLP-1 receptor agonist or composition thereof can protect a subject from the effects induced by an increase in GFAP.

91. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 90, wherein the subject's motor, learning, memory and cognitive skills are improved relative to a control.

92. A GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 91, wherein relative to a control, in the subject, synapses and / or synaptic function are protected, neurogenesis is enhanced, apoptosis is reduced, neurons are protected from oxidative stress, neuroinflammation is reduced, plaque formation is reduced, and chronic inflammatory responses are prevented.

93. The GLP-1 receptor agonist or composition thereof according to any one of claims 63 to 92, wherein: The GLP-1 receptor agonist is a derivative of a GLP-1 polypeptide analog; preferably, the derivative of the GLP-1 polypeptide analog contains a fatty acid modification; more preferably, N-ε 30 -[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(s)-carboxybutanoylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl](Val 8 Glu 22 Lys 30 Arg 26,34 -GLP-1(7-37)) peptide.

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