Uses of peptides as therapeutic agents for degenerative brain diseases

Abstract

This invention relates to the use of peptides as therapeutic agents for degenerative brain diseases. Specifically, it confirms that the peptides of this invention, by targeting microglia, induce microglia in an inflammatory state to an anti-inflammatory state in a disease environment, thereby reducing neuroinflammation and enhancing phagocytic function to clear amyloid-β. Furthermore, in animal models of degenerative brain diseases, the effects of reducing amyloid-β, restoring synaptic plasticity, and improving cognitive impairments related to anxiety, learning, and memory have been confirmed. Therefore, the peptides of this invention can be effectively used as active ingredients in compositions for the prevention or treatment of degenerative brain diseases and the resulting cognitive, learning, or memory impairments.

Description

Technical Field

[0001] This invention relates to the use of polypeptides as therapeutic agents for degenerative brain diseases, and more specifically to the use of polypeptides having a trimer structure composed of the amino acids shown in SEQ ID NO:1 as therapeutic agents for degenerative brain diseases. Background Technology

[0002] Degenerative brain diseases are brain diseases that occur with age and can be differentiated based on their main symptoms and the brain regions affected. Representative degenerative brain diseases include Alzheimer's disease and Parkinson's disease. It is known that degenerative brain diseases are caused by age-related neurodegeneration, as well as by genetic and environmental factors leading to protein accumulation and ultimately, nerve cell death.

[0003] Furthermore, it is known that the death or degeneration of specific brain cells in degenerative brain diseases can be transient or a long-term process. Since dead brain cells cannot regenerate, this ultimately leads to fatal loss of brain function. In particular, brain dysfunction accompanied by a progressive decline in cognitive, sensory, motor, and generalized functions can eventually lead to changes in personality and behavior, rendering the patient unable to care for themselves.

[0004] Reports indicate that the activity of microglia and astrocytes is associated with the onset and progression of degenerative brain diseases. Microglia, as the main glial cells of the brain and spinal cord, play a crucial role in maintaining normal brain function and exerting neuroprotective effects, and help clear excess synapses, amyloid-β (Aβ), and neurofibrillary tangles.

[0005] The role of microglia in the pathogenesis of Alzheimer's disease, the most common form of dementia, is gradually being elucidated. For example, in the brains of Alzheimer's patients or mouse models, microglia or monocytes can be observed surrounding amyloid-β. While microglia have the beneficial function of clearing amyloid-β through phagocytosis, they can also cause excessive inflammatory responses, leading to neuronal damage.

[0006] Parkinson's disease is a common degenerative brain disorder with an incidence of approximately 1.2% in people over 65 years of age. The neurodegenerative changes in Parkinson's disease occur in the substantia nigra, accompanied by dopaminergic denervation and the accumulation of Lewy bodies containing α-synuclein. Numerous activated microglia are observed in the parenchymal tissues of Parkinson's patients; microglia are known to mediate inflammatory responses in the central nervous system in Parkinson's disease.

[0007] Huntington's disease, caused by mutations in the huntingtin protein, is characterized by progressive atrophy of the striatum and cortex. Furthermore, pro-inflammatory microglia can be observed early in this disease. The presence of pro-inflammatory microglia in Huntington's disease is closely related to the severity of the disease.

[0008] Thus, as the importance of the role of microglia in degenerative brain diseases has been elucidated, microglia have been proposed as a target for drugs to treat degenerative brain diseases.

[0009] In view of this, the inventors have conducted in-depth research to develop a therapeutic agent for degenerative brain diseases that targets microglia and has effective therapeutic effects while minimizing the side effects associated with the treatment. As a result, a polypeptide with a trimer structure composed of extremely small peptides was prepared, which minimizes the side effects associated with the administration of exogenous substances. It was confirmed that the polypeptide induces the clearance of amyloid-β by reducing inflammatory substances and enhancing phagocytic function in microglia from an inflammatory state to an anti-inflammatory state. Furthermore, the effects of reducing amyloid-β, restoring synaptic plasticity, and improving cognitive impairments related to anxiety, learning, and memory were confirmed in animal models of degenerative brain diseases administered the polypeptide. Therefore, it is demonstrated that the polypeptide of the present invention can be effectively used as an active ingredient in compositions for the prevention or treatment of degenerative brain diseases and the resulting cognitive, learning, or memory impairments, thus completing this application.

[0010] [Existing technical documents] [Patent Literature] Korean Patent Publication No. 10-2021-0055626 [Non-patent literature] Efthymiou, AG and AM Goate, Late onset Alzheimer's diseasegenetics implicates microglial pathways in disease risk. Mol Neurodegener, 2017. 12(1): p. 43. Hong, S., et al. , Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 2016. 352(6286): p. 712-716. Crotti, A. etal ., Mutanthuntingtinpromotesautonomousmicrogliaactivationviamyeloid lineage-determining factors. Nat. Neurosci. 17, 513-521(2014). Summary of the Invention

[0011] Technical issues The present invention aims to provide a composition for the prevention, treatment or improvement of degenerative brain diseases, comprising a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

[0012] Another object of the present invention is to provide a composition for the prevention or treatment of cognitive impairment, learning impairment or memory impairment, comprising a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

[0013] Problem-solving methods To achieve the objectives of this invention, the present invention provides: a pharmaceutical composition for the prevention or treatment of degenerative brain diseases, comprising a polypeptide or a polynucleotide encoding the polypeptide as an active ingredient, consisting of the amino acids shown in SEQ ID NO:1; the use of the polypeptide or the polynucleotide encoding the polypeptide in a pharmaceutical composition for the prevention or treatment of degenerative brain diseases; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of degenerative brain diseases; and a method for treating degenerative brain diseases, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0014] Furthermore, the present invention provides: a health food composition for preventing or improving degenerative brain diseases, comprising a polypeptide or a polynucleotide encoding the polypeptide as an active ingredient, consisting of the amino acids shown in SEQ ID NO:1; the use of the polypeptide or the polynucleotide encoding the polypeptide in a health food composition for preventing or improving degenerative brain diseases; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a health food composition for preventing or improving degenerative brain diseases; and a method for preventing or improving degenerative brain diseases, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0015] Additionally, the present invention provides: a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment, comprising a polypeptide or a polynucleotide encoding the amino acids shown in SEQ ID NO:1 as an active ingredient; use of the polypeptide or the polynucleotide encoding the polypeptide in a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment; use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment; and a method for the prevention or treatment of cognitive impairment, learning disability, or memory impairment, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0016] Furthermore, the present invention provides: a health food composition for improving cognitive ability, learning ability, or memory, comprising a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding the polypeptide as an active ingredient; the use of the polypeptide or the polynucleotide encoding the polypeptide in a health food composition for improving cognitive ability, learning ability, or memory; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a health food composition for improving cognitive ability, learning ability, or memory; and a method for improving cognitive ability, learning ability, or memory, the method comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0017] The effects of the invention In this invention, it was confirmed that the polypeptide with the trimer structure according to the invention crosses the blood-brain barrier (BBB) ​​and acts on target cells, microglia. Furthermore, it was confirmed that the polypeptide induces microglia from an inflammatory state to an anti-inflammatory state in a disease environment, thereby reducing neuroinflammation, enhancing phagocytic function, and inducing the clearance of amyloid-β. Additionally, a reduction in amyloid-β was confirmed in an animal model of Alzheimer's disease administered the polypeptide. Therefore, the polypeptide of the present invention can be effectively used as an active ingredient in compositions for the prevention or treatment of degenerative brain diseases.

[0018] Furthermore, in this invention, in an animal model of Alzheimer's disease administered the polypeptide with the trimer structure according to the invention, restoration of synaptic plasticity and improvement of cognitive impairments related to anxiety, learning, and memory were confirmed; and in an animal model of dementia administered the polypeptide, relief of memory-related cognitive impairment was confirmed. Therefore, the polypeptide of the present invention can be effectively used as an active ingredient in compositions for the prevention or treatment of cognitive impairment, learning disabilities, or memory impairments.

[0019] Furthermore, the polypeptides with the trimer structure according to the present invention are composed of extremely small polypeptides, which can minimize the side effects associated with the administration of exogenous substances. Attached Figure Description

[0020] Figure 1 This is a schematic diagram illustrating a method for inducing an Alzheimer's disease environment in microglia and treating them with a polypeptide KINE-101 with a trimer structure prepared according to an embodiment of the present invention.

[0021] Figure 2 To illustrate the decrease in expression of the inflammatory marker CD86 and the increase in expression of the anti-inflammatory marker CD206 in microglia cultured in an Alzheimer's disease environment after treatment with KINE-101 (ns p>0.05; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001, scale bar: 100 μm).

[0022] Figure 3 To illustrate the reduction in the production of the inflammatory substance nitric oxide (NO) in microglia cultured in an Alzheimer's disease environment after treatment with KINE-101 (ns p>0.05; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001, scale bar: 100 μm).

[0023] Figure 4 To illustrate the intracellular uptake of amyloid-β (Aβ) in microglia cultured in an Alzheimer's disease environment after treatment with KINE-101 (ns p>0.05; *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001, scale bar: 100 μm).

[0024] Figure 5 This is a schematic diagram illustrating the experimental method for determining whether KINE-101 crosses the blood-brain barrier (BBB) ​​in a mouse model.

[0025] Figure 6 A graph showing the BBB permeability of KINE-101 in a mouse model.

[0026] Figure 7 To illustrate the reduction of amyloid-β in the brain by KINE-101 in a mouse model of Alzheimer's disease induced by amyloid-β (ns p>0.05; ***p<0.001).

[0027] Figure 8 This diagram illustrates the administration of KINE-101 and the behavioral experimental procedures in a mouse model of amyloid-β-induced Alzheimer's disease.

[0028] Figure 9A diagram illustrating the method for conducting the elevated-plus maze behavioral experiment using an amyloid-β-induced Alzheimer's disease mouse model.

[0029] Figure 10 A diagram illustrating the method for conducting the Novel Object Recognition Test (NORT) using an amyloid-β-induced Alzheimer's disease mouse model.

[0030] Figure 11 A figure illustrating the method of performing the Object Location Test (OLT) using an amyloid-β-induced Alzheimer's disease mouse model.

[0031] Figure 12 Figure showing the results of the elevated cross maze behavioral experiment in a mouse model of Alzheimer's disease induced by KINE-101 administration of amyloid-β (*p<0.05; **p<0.01).

[0032] Figure 13 Figure showing the results of the novel object recognition experiment in a mouse model of Alzheimer's disease induced by KINE-101 administration of amyloid-β (*p<0.05).

[0033] Figure 14 Figure showing the results of the object position test in a mouse model of Alzheimer's disease induced by KINE-101 administration of amyloid-β (*p<0.05).

[0034] Figure 15 This figure illustrates the method and results for measuring long-term potentiation (LTP) after administration of KINE-101 in an amyloid-β-induced Alzheimer's disease mouse model. Specifically, Figure 15 A is a schematic diagram of the mouse hippocampus and the mechanism of pop-spike generation. Figure 15 Figure B shows an example of a pop-spike and its amplitude measurement method. Figure 15 C shows the change in pop-spike amplitude over time in a mouse model of amyloid-β-induced Alzheimer's disease, depending on whether KINE-101 was administered. Figure 15 Figure D shows the results of LTP recovery by KINE-101 in an amyloid-β-induced Alzheimer's disease mouse model (**p<0.01).

[0035] Figure 16The diagram illustrates the method and results of analyzing sharp-wave ripples (SWR) after administration of KINE-101 in a mouse model of amyloid-β-induced Alzheimer's disease. Specifically, Figure 16 Figure A shows examples of SWR at different frequencies. Figure 16 Figure B shows that KINE-101 increased the frequency of SWR in an amyloid-β-induced Alzheimer's disease mouse model. Figure 16 C is a graph showing that KINE-101 increased the SWR intensity in an amyloid-β-induced Alzheimer's disease mouse model (*p<0.05).

[0036] Figure 17 To demonstrate a method for performing the Y-maze test using a scopolamine-induced dementia mouse model. Figure 17 A and Figure 17 B) and test results Figure 17 The graph of C) (ns p>0.05; *p<0.05; ****p<0.0001; ##p<0.01). Detailed Implementation

[0037] The present invention will now be described in more detail.

[0038] The present invention provides a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding the polypeptide.

[0039] In this invention, "peptide" refers to a polymer composed of two or more amino acids linked by amide bonds (or peptide bonds). Although various studies have been conducted on peptide therapeutics, the large size of peptides themselves leads to the generation of antibodies against the peptide drug and induces immune responses, resulting in reduced efficacy and side effects. The technical significance of this invention lies in its identification of a pharmacologically effective peptide with a trimer structure composed of fewer than 10 amino acids.

[0040] The polypeptide of the present invention may be composed of the amino acids shown in SEQ ID NO:1, and may contain amino acid sequences having sequence homology of 75% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more with the amino acid sequence shown in SEQ ID NO:1. More specifically, the polypeptide of the present invention may contain amino acid sequences having sequence homology of 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% or more with the amino acid sequence shown in SEQ ID NO:1.

[0041] In addition, the polypeptides of the present invention may further include a targeting sequence, a tag, labeled residues, and an amino acid sequence prepared for a specific purpose of increasing half-life or polypeptide stability.

[0042] Furthermore, the polypeptides of the present invention can be obtained by various methods known in the art. For example, they can be prepared using polynucleotide recombination and protein expression systems, synthesized in vitro by chemical synthesis such as polypeptide synthesis, or prepared by cell-free protein synthesis methods.

[0043] Furthermore, to achieve better chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad bioactivity spectrum), and reduced antigenicity, a protecting group can be attached to the N-terminus or C-terminus of the peptide. Examples of such protecting groups include acetyl, fluorenyl methoxycarbonyl, formyl, palmitoyl, myristoyl, stearoyl, or polyethylene glycol (PEG), but any component capable of modifying the peptide, particularly enhancing its stability, can be included without limitation.

[0044] The term "stability" as used in this invention refers not only to in vivo stability that protects the polypeptides of this invention from attack by proteases in vivo, but also to storage stability (e.g., room temperature storage stability).

[0045] The term "polynucleotide" as used in this invention refers to a polymer of nucleotides that functions to transmit genetic information. For the purposes of this invention, the polynucleotide encodes the polypeptide of SEQ ID NO:1 and may include sequences having at least 75%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% sequence homology to the polynucleotide sequence encoding the polypeptide.

[0046] The term “homology” as used in this invention refers to the degree of similarity to a wild-type amino acid sequence or polynucleotide sequence. Such comparisons of homology can be performed using comparison procedures known in the art, and the homology between two or more sequences can be calculated as a percentage (%).

[0047] Furthermore, the present invention provides: a pharmaceutical composition for the prevention or treatment of degenerative brain diseases, comprising a polypeptide or a polynucleotide encoding the polypeptide as an active ingredient, consisting of the amino acids shown in SEQ ID NO:1; the use of the polypeptide or the polynucleotide encoding the polypeptide in a pharmaceutical composition for the prevention or treatment of degenerative brain diseases; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of degenerative brain diseases; and a method for treating degenerative brain diseases, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0048] The term "prevention" as used in this invention refers to all actions that suppress or delay the onset of a disease by applying a pharmaceutical composition according to the invention.

[0049] The term "treatment" as used in this invention refers to all actions that improve or beneficially alter the symptoms of a disease by administering a pharmaceutical composition according to the invention.

[0050] In this invention, "individual" refers to the object that needs to be treated for a disease, and more specifically to mammals, such as humans or non-human primates, rodents (mice, rats), dogs, cats, horses, and cattle.

[0051] In this invention, the degenerative brain disease can be, but is not limited to, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, amyloid stroke, systemic amyloidosis, Dutch amyloidosis, Pick's disease, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, or frontotemporal dementia.

[0052] In this invention, the composition targets microglia, and microglia can be used as a target to prevent or treat the degenerative brain disease through the following properties: i) Alleviating neuroinflammation by inducing microglia from an inflammatory state to an anti-inflammatory state; and ii) Clearing amyloid-β by activating the phagocytic function of microglia.

[0053] Specifically, the composition can cross the blood-brain barrier (BBB) ​​and target microglia in the brain, reducing neuroinflammation by inducing the state of inflammatory microglia to an anti-inflammatory state, and also clearing amyloid-β, a toxic protein, by enhancing phagocytic function, thereby preventing or treating the degenerative brain disease.

[0054] In a specific embodiment of the present invention, the inventors prepared a trimer-structured polypeptide KINE-101 using PSP monomer fragments and confirmed that KINE-101 targets microglia, reduces inflammatory substances by inducing microglia from an inflammatory state to an anti-inflammatory state, and induces the clearance of amyloid-β by enhancing phagocytic function.

[0055] Furthermore, the inventors confirmed that KINE-101 can reduce amyloid-β in the brains of Alzheimer's disease mouse models, restore synaptic plasticity, and improve cognitive impairments related to anxiety, learning, and memory. Additionally, it was confirmed that KINE-101 can alleviate memory-related cognitive impairment in dementia mouse models.

[0056] Therefore, the inventors have confirmed that the polypeptide of the present invention targets microglia, activates the phagocytic function of microglia, thereby clearing amyloid-β and inducing microglia in an inflammatory state to an anti-inflammatory state; and have confirmed that in animal models of degenerative brain diseases, it reduces amyloid-β, restores synaptic plasticity, and improves cognitive impairments related to anxiety, learning, and memory. Therefore, the polypeptide of the present invention can be effectively used as an active ingredient in pharmaceutical compositions for the prevention or treatment of degenerative brain diseases.

[0057] The polypeptides or polynucleotides encoding the polypeptides of the present invention can be loaded in pharmaceutically acceptable carriers, such as colloidal suspensions, powders, saline solutions, lipids, liposomes, microspheres, or nanospheres. They can form complexes with or bind to delivery carriers and can be delivered in vivo using delivery systems known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendritic polymers, saponins, adsorption enhancers, or fatty acids.

[0058] In addition, pharmaceutically acceptable carriers may include, but are not limited to, commonly used ingredients in formulations such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, resin, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Furthermore, in addition to the above-mentioned components, lubricants, humectants, sweeteners, flavoring agents, emulsifiers, suspending agents, and preservatives may also be included.

[0059] The pharmaceutical compositions of the present invention can be administered orally or enterally (e.g., intramuscular, intravenous, intraperitoneal, subcutaneous, intradermal, or local) according to the desired method. The dosage may vary depending on the patient's condition and weight, the severity of the disease, the form of the drug, the route of administration, and the timing, but may be appropriately selected by those skilled in the art.

[0060] The pharmaceutical compositions of the present invention are administered in pharmaceutically effective amounts. In this invention, "pharmaceutically effective amount" refers to a sufficient amount to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment. The effective dose level can be determined based on factors such as the patient's disease type, severity, drug activity, drug sensitivity, timing of administration, route of administration and excretion rate, treatment duration, concurrent medications, and other factors known in the medical field. The pharmaceutical compositions of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, simultaneously, separately, or sequentially with conventional therapeutic agents, and can be administered once or multiple times. Importantly, after considering all the above factors, the dosage is administered to achieve the maximum effect with the minimum amount without producing side effects, which can be readily determined by those skilled in the art.

[0061] Specifically, the effective amount of the pharmaceutical composition of the present invention can vary depending on the patient's age, gender, condition, weight, absorption rate, inactivation rate, excretion rate of the active ingredient in the body, disease type, and combination of drugs, and can be increased or decreased according to the route of administration, degree of obesity, gender, weight, age, etc.

[0062] Furthermore, the present invention provides: a health food composition for preventing or improving degenerative brain diseases, comprising a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding the polypeptide as an active ingredient; the use of the polypeptide or the polynucleotide encoding the polypeptide in a health food composition for preventing or improving degenerative brain diseases; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a health food composition for preventing or improving degenerative brain diseases; and a method for preventing or improving degenerative brain diseases, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0063] The term “improvement” as used in this invention refers to any action that at least reduces parameters (e.g., symptom severity) related to the condition being treated.

[0064] In this invention, the contents concerning the polypeptides, polynucleotides, and degenerative brain diseases are the same as those described above. Therefore, the specific description refers to the above contents, and the following only describes the unique composition of the health food composition.

[0065] Furthermore, the inventors confirmed that the polypeptide of the present invention targets microglia, activates the phagocytic function of microglia, clears amyloid-β, and induces microglia in an inflammatory state to an anti-inflammatory state; and confirmed that in animal models of degenerative brain diseases, it has the effects of reducing amyloid-β, restoring synaptic plasticity, and improving cognitive impairments related to anxiety, learning, and memory. Therefore, the polypeptide of the present invention can be effectively used as an active ingredient in health food compositions for the prevention or improvement of degenerative brain diseases.

[0066] The health food composition of the present invention can be used simultaneously or separately with a therapeutic agent in the prevention or improvement of a disease, before or after the onset of the disease.

[0067] In the health food composition of the present invention, the active ingredients can be added directly to the food or used in combination with other foods or food ingredients, and can be used appropriately according to conventional methods. The amount of the active ingredients can be appropriately determined according to its intended use (prevention or improvement). Generally, when manufacturing food or beverages, the composition of the present invention can be added in an amount preferably less than 15% by weight, more preferably less than 10% by weight, relative to the raw materials. However, in the case of long-term intake for health and hygiene purposes or for health regulation purposes, the amount can be below the range mentioned above.

[0068] In addition to the aforementioned active ingredients, the health food composition of the present invention may, without particular limitation, contain other ingredients as essential components. For example, it may contain various flavoring agents or natural carbohydrates as additional ingredients, similar to ordinary beverages. Examples of the aforementioned natural carbohydrates may be monosaccharides, such as glucose and fructose; disaccharides, such as maltose and sucrose; and polysaccharides, such as conventional sugars like dextrin and cyclodextrin; as well as sugar alcohols, such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (such as sematrandrine and stevia extract (e.g., rebaudioside A and glycyrrhizin)) and synthetic flavoring agents (such as saccharin and aspartame) may be advantageously used. The ratio of the aforementioned natural carbohydrates may be appropriately determined according to the selection of those skilled in the art.

[0069] In addition to the aforementioned ingredients, the health food composition of the present invention may also contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, and carbonating agents used in carbonated beverages. These ingredients may be used alone or in combination, and the ratio of these additives may be appropriately selected by those skilled in the art.

[0070] Furthermore, the present invention provides: a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment, comprising a polypeptide or a polynucleotide encoding the amino acids shown in SEQ ID NO:1 as an active ingredient; the use of the polypeptide or the polynucleotide encoding the polypeptide in a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment; and a method for the prevention or treatment of cognitive impairment, learning disability, or memory impairment, comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0071] The term "cognitive impairment" used in this invention refers to abnormalities in cognitive abilities related to the way of acquiring, remembering and using knowledge. Cognitive abilities include cognitive functions such as knowledge, memory, comprehension, thinking, problem-solving, critical thinking and creativity.

[0072] The term "learning disability" as used in this invention refers to a disability that manifests significant difficulties in learning functions such as listening, speaking, attention, perception, memory, and problem-solving, or in academic achievement areas such as reading, writing, and mathematics.

[0073] The term "memory impairment" as used in this invention refers to a state in which one is unable to remember newly acquired facts, unable to remember the names of things or people, or has difficulty or inability to recall past experiences.

[0074] Such cognitive impairments, learning disabilities, or memory impairments can be caused by a variety of factors and environments, and in this invention, the causes are not particularly limited. For example, they may be caused by degenerative brain diseases such as Alzheimer's disease, dementia, mild cognitive impairment, cognitive deficits, and attention deficits.

[0075] In this invention, the contents concerning the polypeptides, polynucleotides, degenerative brain diseases, and pharmaceutical compositions are the same as described above, and therefore the specific description refers to the above contents.

[0076] Furthermore, the inventors have confirmed that the polypeptides of the present invention have the effect of restoring synaptic plasticity and improving cognitive impairments related to anxiety, learning, and memory in animal models of degenerative brain diseases. Therefore, the polypeptides of the present invention can be effectively used as an active ingredient in pharmaceutical compositions for the prevention or treatment of cognitive impairment, learning disabilities, or memory impairments.

[0077] Furthermore, the present invention provides: a health food composition for improving cognitive ability, learning ability, or memory, comprising a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding the polypeptide as an active ingredient; the use of the polypeptide or the polynucleotide encoding the polypeptide in a health food composition for improving cognitive ability, learning ability, or memory; the use of the polypeptide or the polynucleotide encoding the polypeptide in the preparation of a health food composition for improving cognitive ability, learning ability, or memory; and a method for improving cognitive ability, learning ability, or memory, the method comprising administering the polypeptide or the polynucleotide encoding the polypeptide to an individual.

[0078] In this invention, the contents concerning the polypeptides, polynucleotides, degenerative brain diseases, and health food compositions are the same as those described above, and therefore the specific description refers to the above contents.

[0079] Furthermore, the inventors have confirmed that the polypeptides of the present invention have the effect of restoring synaptic plasticity and improving cognitive impairments related to anxiety, learning, and memory in animal models of degenerative brain diseases. Therefore, the polypeptides of the present invention can be effectively used as an active ingredient in health food compositions that improve cognitive ability, learning ability, or memory.

[0080] The present invention will now be described in detail through examples.

[0081] However, the following embodiments are merely illustrative of the present invention, and the content of the present invention is not limited to the following embodiments.

[0082] [Example 1] Preparation of polypeptides In this embodiment, the trimer polymer KINE-101 was prepared using PSP monomers, as shown in Table 1. The synthesized peptide was then separated and purified using high-performance liquid chromatography (SHIMADZU Prominence HPLC) with a Shiseido Capcell Pak C18 column (4.6 × 50 mm). Furthermore, the quality of the synthesized peptide was confirmed using mass spectrometry (AXIMAAssurance, MALDI-TOF, Shimadzu).

[0083] [Table 1]

[0084] [Example 2] Confirmation of KINE-101's enhancement of anti-inflammatory and phagocytic functions of microglia in an Alzheimer's disease setting. While microglia clear various foreign substances, including amyloid-beta, through phagocytosis, they are known to participate in degenerative brain diseases through chronic inflammatory responses or overactivation of synaptic pruning. Therefore, the efficacy of KINE-101 was confirmed by targeting microglia cultured in an Alzheimer's disease environment.

[0085] Specifically, such as Figure 1 As shown, cultured human microglia (hMG) were treated with 1 μM of amyloid-β (Aβ), an oligomeric form of Alzheimer's disease and 10 ng / mL of interferon-γ (IFNγ), an inflammatory substance, to construct an environment conducive to Alzheimer's disease, the leading cause of dementia. Under these conditions, KINE-101 prepared in [Example 1] was administered at concentrations of 1, 5, 10, 100, or 500 ng / mL. The culture medium was changed after two days, and the same drugs were administered again.

[0086] Two days later, to investigate whether microglia were induced to transition from an inflammatory state (M1) to an anti-inflammatory state (M2), cells were fixed with fixative and labeled with antibodies against the inflammatory marker CD86 and the anti-inflammatory marker CD206. Subsequently, staining was performed using fluorescently labeled secondary antibodies. Images were acquired using fluorescence microscopy, and the fluorescence signals were quantified using software to compare the degree of change from an inflammatory to an anti-inflammatory state induced by KINE-101. Figure 2 ).

[0087] In addition, to evaluate the effect of KINE-101 on reducing inflammatory substances, NO (nitric oxide), an inflammatory substance that plays an important role in the progression of Alzheimer's disease and is present in cells, was stained with difluorofluorescein-FM diacetate, and images were acquired using fluorescence microscopy. To quantify the intensity of the fluorescence signal, software analysis was used to confirm the degree of NO reduction induced by KINE-101. Figure 3 ).

[0088] Furthermore, to investigate the extent to which KINE-101 enhances the phagocytic function of microglia, the intracellular amyloid-β was quantified. Amyloid-β was labeled as a pH-sensitive red fluorescent substance, characterized by fluorescence due to the low pH (pH 3-5) of lysosomes—intracellular organelles involved in protein degradation—when it migrates to them. Therefore, the fact that it emits red fluorescence intracellularly indicates that amyloid-β, after migrating to microglia via phagocytosis, is being broken down in lysosomes. Images of the red fluorescence were acquired using fluorescence microscopy and quantified and compared using software programs. Figure 4 ).

[0089] The result, such as Figure 2 As shown, KINE-101 decreased the inflammatory marker CD86 in microglia cultured in an Alzheimer's disease setting in a concentration-dependent manner, while increasing the anti-inflammatory marker CD206. These results indicate that KINE-101 has the function of inducing microglia in an inflammatory state to an anti-inflammatory state in a degenerative brain disease setting.

[0090] In addition, such as Figure 3 As shown, KINE-101 reduced the production of the inflammatory substance NO in microglia cultured in an Alzheimer's disease environment in a concentration-dependent manner. These results indicate that KINE-101 has anti-inflammatory efficacy in reducing the increase of intracellular inflammatory substances in microglia in the context of degenerative brain disease.

[0091] In addition, such as Figure 4 As shown, in microglia cultured in an Alzheimer's disease environment, the intracellular migration of amyloid-β increased in dependence on KINE-101 concentration. These results indicate that KINE-101 has the effect of enhancing the phagocytic function of microglia.

[0092] The results above indicate that KINE-101 targets microglia in an inflammatory state within the context of Alzheimer's disease, inducing them into an anti-inflammatory state, thereby reducing inflammatory substances and enhancing phagocytic function to induce the clearance of amyloid-β.

[0093] [Example 3] KINE-101 crosses the blood-brain barrier in an animal model. In the treatment of degenerative brain diseases, the blood-brain barrier (BBB) ​​constitutes a significant obstacle to drug delivery. Due to the structural specificity of capillaries in the brain, the BBB prevents most drugs from being delivered to target cells. Therefore, to determine whether KINE-101 can cross the BBB and act on target cells in degenerative brain diseases, KINE-101 was administered to a mouse model to confirm its ability to cross the BBB.

[0094] Specifically, such as Figure 5 As shown, after intravenously injecting FITC-labeled KINE-101 20 mg / kg into the tail of 8-week-old male C57BL / 6 mice, the fluorescence signal in the brain was measured at time points using a bioimaging device. Figure 6 ).

[0095] The result, such as Figure 6 As shown, fluorescent signals were observed in the brain starting 10 seconds after KINE-101 administration, with the strongest signal confirmed after 10 minutes. Furthermore, the fluorescent signal persisted for 2 hours.

[0096] The results above indicate that KINE-101 can pass through the BBB. Based on the confirmed in vitro experimental results, it is expected that KINE-101 passing through the BBB can induce microglia in the brain to an anti-inflammatory state, thereby reducing inflammatory substances and enhancing phagocytic function, and thus inducing the clearance of amyloid-β.

[0097] [Example 4] Confirmation of the efficacy of KINE-101 in an animal model of degenerative brain disease. [4-1] KINE-101 was confirmed to reduce amyloid-β in a mouse model of Alzheimer's disease. To observe the effects of KINE-101 on degenerative brain diseases, changes in amyloid-β expression were confirmed after administration of KINE-101 to a mouse model of Alzheimer's disease induced by amyloid-β.

[0098] Specifically, the 5xFAD mouse model of Alzheimer's disease induced by amyloid-β was obtained from the Jackson Laboratory. This Alzheimer's disease mouse model is known to overexpress human amyloid-β, which oligomerizes extracellularly, eventually precipitating into insoluble protein clumps and damaging nerve cells, thus inducing dementia. Therefore, the 4-month-old 5xFAD mice induced by amyloid-β were administered KINE-101 prepared in [Example 1] at a dose of 50 mg / kg or 100 mg / kg twice weekly via tail vein injection. After 4 weeks, the mouse brain tissue was sectioned using a vibratome, and amyloid-β was detected using a fluorescent (FITC dye) antibody, with images acquired by fluorescence microscopy. Figure 7 A), and analyzed using Cytation5 software to quantify the amount of amyloid-β deposited in brain tissue (A). Figure 7 B).

[0099] The result, such as Figure 7 As shown, in the case of 5xFAD mice, a considerable amount of amyloid-β was deposited throughout the brain tissue. Conversely, amyloid-β was reduced in the brain tissue of mice administered 50 mg / kg of KINE-101. In the group administered KINE-101 at twice the concentration (100 mg / kg), a reduction of approximately 60% or more in amyloid-β in the brain tissue was confirmed.

[0100] The results above indicate that KINE-101 can clear toxic proteins deposited in the brain via the BBB. In particular, considering that KINE-101 increases the uptake of amyloid-β by microglia, the reduction of amyloid-β in the mouse brain is attributed to the phagocytic activity of microglia activated by KINE-101.

[0101] [4-2] The behavioral improvement effect of KINE-101 was confirmed in a mouse model of Alzheimer's disease. To investigate the effects of KINE-101 on anxiety, learning, and memory impairment caused by degenerative brain diseases, behavioral changes were confirmed after administration of KINE-101 to a mouse model of Alzheimer's disease induced by amyloid-β.

[0102] Specifically, such as Figure 8 As shown, 4-month-old 5xFAD mice induced by amyloid-β were subcutaneously injected twice weekly with physiological saline or KINE-101 100 mg / kg prepared in [Example 1] for a total of 2 months. Additionally, normal mice born in the same littermates as the 5xFAD mice were used as a normal control group and were subcutaneously injected with physiological saline in the same manner as described above.

[0103] After the administration of the medication, if Figure 9As shown, a behavioral experiment was conducted using an elevated-plus maze to assess the presence of anxiety disorder behaviors. The elevated-plus maze apparatus was designed to be 40 cm above the ground, with two opposite arms being closed arms with walls, and the remaining two being open arms without walls. This behavioral experiment utilizes the instinctive avoidance behavior of chordates when they perceive a threat of fall in a height without any protective devices. The time spent by the experimental animal in the open arms where it felt threatened was compared to the time spent in the closed arms where it felt relatively safe, thus determining whether the animal had an anxiety disorder. Compared to the normal control group, a very low preference for open arms indicated a hyper-anxiety model, while a high preference for open arms indicated a hyper-anxiety disorder. Alzheimer's disease animal models are known to exhibit hyper-anxiety characteristics. This behavior is reportedly a result of the coordinated action of the brain's amygdala and hippocampus, which are responsible for threat perception and danger assessment. Before the behavioral experiment, the animals underwent a acclimatization process of at least one hour in the experimental space. Then, the animals were allowed to explore the maze freely, one by one, without any interference. Video recordings were used to record which arm each animal stayed in for more than five minutes. The time spent in the open arms without any protective barriers was then compared to quantitatively determine whether the animals exhibited anxiety-related behaviors. Figure 12 ).

[0104] In addition, to investigate whether KINE-101 could improve memory-related cognitive impairments, a novelty object recognition (NORT) experiment was conducted to test object memory. NORT is a testing method that utilizes the tendency of curious laboratory animals to be more interested in and spend more time exploring new objects. Figure 10 As shown, after placing two objects in the test space, experimental animals were allowed to explore to induce memory formation. Then, one of the objects was replaced with a new object, and the time taken for the animal to remember the original object and explore the new one was measured. Additionally, the discrimination index was calculated using the following formula (…). Figure 13 Differentiation index = New object exploration time / (New object exploration time + Existing object exploration time).

[0105] In addition, to determine whether spatial memory, a representative cognitive impairment in Alzheimer's patients, had improved, the Object Placement Test (OLT) was conducted. Similar to the Norelation Test (NORT), the OLT involves experimental animals exploring two objects, but... Figure 11As shown, the object is not replaced with a new one, but only its position is changed. This test method also uses curious experimental animals, inducing the remodeling of place cells in the hippocampus by moving the object, thereby observing whether the exploration time of the new space increases. The discrimination index is calculated using the following formula ( Figure 14 Distinguishing index = Spatial exploration time of object movement / (Spatial exploration time of object movement + Spatial exploration time of object still movement).

[0106] The result, such as Figure 12 As shown, the behavioral assessment results of anxiety disorders indicated that, compared with the Alzheimer's disease induction group [5xFAD(solvent)], the KINE-101 administration group [5xFAD(KINE-101)] had a significantly shorter residence time in the open arm, confirming that it was at a similar level to the normal control group [Veh-Littermate control(solvent)].

[0107] In addition, such as Figure 13 As shown, NORT results indicated that, compared to the Alzheimer's disease-inducing group [5xFAD(solvent)], the KINE-101-administered group [5xFAD(KINE-101)] spent more time exploring new objects during the 2-month administration period. These results suggest that KINE-101 administration helps in the recovery of object memory impairment.

[0108] In addition, such as Figure 14 As shown, OLT results indicated that, compared to the Alzheimer's disease-inducing group [5xFAD(solvent)], the KINE-101-administered group [5xFAD(KINE-101)] spent more time exploring new spaces after object movement during the 2-month administration period. These results suggest that KINE-101 administration helps in the recovery of spatial memory impairment.

[0109] The results above show that KINE-101 effectively improves cognitive impairments related to anxiety, learning, and memory in degenerative brain diseases such as Alzheimer's disease.

[0110] [4-3] KINE-101 was confirmed to enhance synaptic plasticity and thereby restore cognitive function in a mouse model of Alzheimer's disease. In the formation of episodic memory, the conversion from short-term to long-term memory relies on the hippocampus, a region of the brain, and synaptic plasticity is a representative memory mechanism of the hippocampus. Specifically, information transmission between nerve cells, the basic units of the brain, occurs through synaptic plasticity, which is known to be a core mechanism for learning and memory formation. Therefore, to investigate the effects of KINE-101 on memory impairment induced by degenerative brain diseases, KINE-101 was administered to a mouse model of Alzheimer's disease induced by amyloid-β, and the restoration of synaptic plasticity was confirmed.

[0111] Specifically, using the mouse model described in Examples [4-2] above, long-term potentiation (LTP) was measured by electrophysiological analysis. Brief high-frequency stimulation (TBS) was applied, and the amplitude of the pop-spike potential before stimulation (baseline) and 25 minutes later was compared, with the results used as LTP. To measure LTP, mice were anesthetized, and an electrical signal, i.e., a pop-spike, was generated in the hippocampus of the anesthetized mice. Figure 15 ).

[0112] Furthermore, the replay mechanism, which is enhanced by spatial memory cells to convert into long-term memory, is observed in experimental animals when they cease exploration, manifesting as sequential burst activation of hippocampal neurons. This phenomenon is termed SWR (sharp-wave ripples) based on signal morphology. To confirm whether spatial memory generation ability is restored in an Alzheimer's disease mouse model after KINE-101 administration, the frequency and intensity of SWR were compared and analyzed. SWR was calculated by measuring continuous electrophysiological signals using electrodes implanted in the hippocampus, and then determining the frequency (Event / s) and intensity (μV²) of signals exceeding a threshold (4 times the standard deviation) at specified frequencies (sharp waves: 1–50 Hz, ripples: 125–250 Hz). Figure 16 ).

[0113] The result, such as Figure 15As shown, LTP measurement results indicated that LTP was decreased in the Alzheimer's disease-inducing group [5xFAD (solvent)] compared to the normal control group [Wild-Littermate control (solvent)], while LTP was increased in the KINE-101-treated group [5xFAD (KINE-101)] compared to the Alzheimer's disease-inducing group. These results suggest that KINE-101 restored LTP, thus restoring synaptic plasticity.

[0114] In addition, such as Figure 16 As shown, SWR analysis confirmed that the frequency and intensity of SWR were increased in the KINE-101-treated group [5xFAD(KINE-101)] compared to the Alzheimer's disease-induced group [5xFAD(solvent)]. These results suggest that KINE-101 helps restore SWR, which reflects the activity of spatial memory cells.

[0115] The results above indicate that KINE-101 helps improve object memory and spatial memory abilities in degenerative brain diseases such as Alzheimer's by restoring synaptic plasticity in the hippocampus and promoting the formation mechanism of spatial memory cells.

[0116] [4-4] Confirming the efficacy of KINE-101 in a mouse model of dementia To investigate the effects of KINE-101 on learning and memory impairment caused by dementia resulting from degenerative brain disease, mice were administered KINE-101 and scopolamine to induce dementia, followed by a Y-maze test.

[0117] Specifically, scopolamine, as a competitive antagonist of the neurotransmitter acetylcholine, binds to acetylcholine receptors expressed in nerve cells and is known to cause cognitive impairment, including in learning and memory, when administered to animals. In particular, scopolamine is known to damage nerve cells by activating microglia, increasing inflammatory cytokines, and oxidative stress. Additionally, the Y-maze test is a behavioral experiment designed to assess the working memory of animals, taking into account the high affinity of mice for novel environments. Figure 17 A). Therefore, as Figure 17 As shown in B, 8-week-old male C57BL / 6 mice were divided into 4 groups. According to the conditions in Table 2, each group received subcutaneous injections of KINE-101 (experimental group) or PBS (negative control group) twice weekly for 2 weeks. Four days later, scopolamine was injected intraperitoneally. Thirty minutes after scopolamine administration, the mice were placed in a Y-shaped maze. The order in which they entered each arm was recorded within 5 minutes, and the number of times they entered different arms was calculated to quantify the spontaneous alternation rate (%Alternation). Figure 17 C).

[0118] [Table 2]

[0119] As a result, Figure 17 As shown, the proportion of mice entering the same arm was higher and the spontaneous alternation rate was lower in the scopolamine-treated group [Vehicle (PBS)], while the proportion entering a new arm was higher in the positive control group [Control]. The spontaneous alternation rate in the KINE-101-treated group [KINE-101] was statistically significantly higher, confirming a concentration-dependent trend. In particular, the spontaneous alternation rate in the 100 mg / kg KINE-101-treated group [KINE-101, 100 mg / kg] was similar to that in the positive control group. On the other hand, the total number of arm entries was similar regardless of whether the drug was administered, which means that the drug does not affect the motor neurons of the mice, and the above results are not artifacts caused by changes in the motor neurons of the mice. The above results indicate that KINE-101 can alleviate the learning and memory impairment caused by neurological damage under the inflammatory and oxidative stress environment induced by scopolamine, and it can be seen that KINE-101 can also exert the same effect in other dementia-causing degenerative brain diseases with similar etiological environments, thereby alleviating cognitive impairment.

[0120] Industrial applicability The peptides of this invention target microglia, inducing them into an anti-inflammatory state in a disease environment, thereby reducing neuroinflammation and enhancing their phagocytic function, exhibiting an effect of clearing amyloid-β. Furthermore, in animal models of degenerative brain diseases, they demonstrate effects of reducing amyloid-β, restoring synaptic plasticity, and improving cognitive impairments related to anxiety, learning, and memory. Therefore, the peptides of this invention can be effectively used as an active ingredient in compositions for the prevention or treatment of degenerative brain diseases and the resulting cognitive, learning, or memory impairments.

Claims

1. A pharmaceutical composition for the prevention or treatment of degenerative brain diseases, comprising a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

2. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 1, characterized in that, The N-terminus or C-terminus of the polypeptide is bound to at least one protecting group selected from the group consisting of acetyl, fluorenylmethoxycarbonyl, formyl, palmitoyl, myristoyl, stearoyl and polyethylene glycol (PEG).

3. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 1, characterized in that, The degenerative brain disease is selected from at least one of the following groups: dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, amyloid stroke, systemic amyloidosis, Dutch amyloidosis, Pick's disease, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, and frontotemporal dementia.

4. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 1, characterized in that, The composition is capable of crossing the blood-brain barrier.

5. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 1, characterized in that, The composition targets microglia.

6. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 5, characterized in that, The composition targets microglia and has the following properties: i) Inducing microglia from an inflammatory state to an anti-inflammatory state, thereby reducing neuroinflammation; and ii) Clear amyloid-β by activating the phagocytic function of microglia.

7. The pharmaceutical composition for the prevention or treatment of degenerative brain diseases according to claim 1, characterized in that, The composition is formulated as a preparation for oral, intramuscular, intravenous, intraperitoneal, subcutaneous, intradermal, or local administration.

8. A health food composition for the prevention or improvement of degenerative brain diseases, comprising a polypeptide composed of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

9. A pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability, or memory impairment, comprising a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

10. A health food composition for improving cognitive ability, learning ability or memory, comprising a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide as an active ingredient.

11. A method for treating degenerative brain diseases, comprising administering to an individual a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide.

12. A method for preventing or improving degenerative brain diseases, comprising administering to an individual a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide.

13. A method for preventing or treating cognitive impairment, learning disability, or memory impairment, comprising administering to an individual a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide.

14. A method for improving cognitive ability, learning ability, or memory, comprising administering to an individual a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide.

15. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in a pharmaceutical composition for the prevention or treatment of degenerative brain diseases.

16. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in a health food composition for the prevention or improvement of degenerative brain diseases.

17. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability or memory impairment.

18. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in a health food composition for improving cognitive ability, learning ability or memory.

19. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of degenerative brain diseases.

20. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in the preparation of a health food composition for the prevention or improvement of degenerative brain diseases.

21. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in the preparation of a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability or memory impairment.

22. Use of a polypeptide consisting of the amino acids shown in SEQ ID NO:1 or a polynucleotide encoding said polypeptide in the preparation of a health food composition for improving cognitive ability, learning ability or memory.

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