Use of peptide as therapeutic agent for degenerative brain diseases

Abstract

The present invention relates to use of a peptide as a therapeutic agent for degenerative brain diseases. Specifically, it was identified that the peptide of the present invention targeted microglia to induce the state of inflammatory microglia to be an anti-inflammatory state in a disease environment, thereby reducing neuroinflammation and increasing a phagocytosis function, leading to an effect of removing amyloid beta protein, and the peptide of the present invention exhibited effects of reducing amyloid-beta, recovering synaptic plasticity, and alleviating cognitive disorders related to anxiety, learning, and memory in a degenerative brain disease animal model. Therefore, the peptide of the present invention can be helpfully used as an active ingredient of a composition for preventing or treating degenerative brain diseases, and the resulting cognitive disorders, learning disorders, or memory disorders.

Description

Use of peptides as therapeutics for degenerative brain diseases

[0001] The present invention relates to the use of a peptide as a therapeutic agent for a degenerative brain disease, and more particularly, to the use of a trimeric peptide composed of an amino acid represented by sequence number 1 as a therapeutic agent for a degenerative brain disease.

[0002] Degenerative brain diseases, among the degenerative diseases that occur with age, refer to diseases that originate in the brain. They can be categorized based on their primary symptoms and the affected brain region. Representative examples include Alzheimer's disease and Parkinson's disease. Degenerative brain diseases are known to be caused by neurodegeneration due to aging, as well as by protein aggregation and neuronal death caused by genetic and environmental factors.

[0003] In addition, degenerative brain diseases are known to occur when specific brain cells die or degenerate temporarily or over a long period of time, and because dead brain cells cannot be regenerated, they ultimately lead to fatal loss of brain function. In particular, brain dysfunction accompanied by progressive decline in cognitive function, sensory function, motor function, and systemic function ultimately leads to changes in personality and behavior, and patients reach a point where they are unable to take care of themselves.

[0004] The activity of microglia and astrocytes has been reported to be associated with the onset and progression of neurodegenerative diseases. Microglia, the primary glial cells in the brain and spinal cord, play a crucial role in maintaining normal brain function and neuroprotection, removing excessive synapses and contributing to the removal of amyloid beta (Aβ) and neurofibrillary tangles.

[0005] The role of microglia in the pathogenesis of Alzheimer's disease, the most common form of dementia, is being elucidated. For example, microglia and monocytes have been observed surrounding amyloid beta in the brains of Alzheimer's patients and mouse models. While microglia have a beneficial function of removing amyloid beta through phagocytosis, they can also induce excessive inflammation, leading to neuronal damage.

[0006] Parkinson's disease is a common neurodegenerative disorder affecting approximately 1.2% of people over the age of 65. Neurodegeneration in Parkinson's disease occurs in the substantia nigra, accompanied by dopaminergic denervation and the accumulation of Lewy bodies containing alpha-synuclein. Activated microglia are abundant in the parenchymal tissue of patients with Parkinson's disease, and microglia are known to mediate the inflammatory response in the central nervous system in Parkinson's disease.

[0007] Huntington's disease, caused by mutations in the Huntington protein, is characterized by progressive atrophy of the striatum and cortex. Furthermore, proinflammatory microglia are observed early in the disease. In Huntington's disease, proinflammatory microglia are closely associated with the severity of the disease.

[0008] As the importance of the role of microglia in degenerative brain diseases is revealed, microglia are being proposed as a target for treatments for degenerative brain diseases.

[0009] Accordingly, the present inventors have made efforts to develop a treatment for degenerative brain diseases that targets microglia and has an effective therapeutic effect while minimizing side effects as a treatment. As a result, a trimeric peptide composed of a very small peptide size was prepared that can minimize side effects caused by the administration of external substances, and it was confirmed that the peptide reduces inflammatory substances by inducing microglia from an inflammatory state to an anti-inflammatory state, and increases phagocytic function to induce the removal of amyloid beta protein. In addition, in an animal model of degenerative brain diseases administered with the peptide, the effects of reducing amyloid beta, restoring synaptic plasticity, and improving cognitive impairment related to anxiety and learning and memory were confirmed. Therefore, the present application has been made by revealing that the peptide of the present invention can be usefully utilized as an active ingredient of a composition for preventing or treating degenerative brain diseases, cognitive impairment, learning impairment, or memory impairment resulting therefrom.

[0010] [Prior Art Literature]

[0011] [Patent Document]

[0012] Republic of Korea Publication Patent No. 10-2021-0055626

[0013] [Non-patent literature]

[0014] Efthymiou, AG and AM Goate, Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Mol Neurodegener, 2017. 12(1): p. 43.

[0015] Hong, S., et al., Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science, 2016. 352(6286): p. 712-716.

[0016] Crotti, A.et al., Mutant huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 17, 513-521(2014).

[0017] The purpose of the present invention is to provide a composition for preventing, treating or improving a degenerative brain disease, which comprises as an active ingredient a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

[0018] Another object of the present invention is to provide a composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising as an active ingredient a peptide consisting of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

[0019] In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a degenerative brain disease, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating a degenerative brain disease; a use of the peptide or the polynucleotide encoding the same for preparing a pharmaceutical composition for preventing or treating a degenerative brain disease; and a method for treating a degenerative brain disease, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0020] In addition, the present invention provides a health functional food composition for preventing or improving a degenerative brain disease, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a health functional food composition for preventing or improving a degenerative brain disease; a use of the peptide or the polynucleotide encoding the same for producing a health functional food composition for preventing or improving a degenerative brain disease; and a method for preventing or improving a degenerative brain disease, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0021] In addition, the present invention provides a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment; a use of the peptide or the polynucleotide encoding the same for preparing a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment; and a method for preventing or treating cognitive impairment, learning disability or memory impairment, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0022] In addition, the present invention provides a health functional food composition for enhancing cognitive ability, learning ability or memory, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a health functional food composition for enhancing cognitive ability, learning ability or memory; a use of the peptide or the polynucleotide encoding the same for manufacturing a health functional food composition for enhancing cognitive ability, learning ability or memory; and a method for enhancing cognitive ability, learning ability or memory, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0023] In the present invention, it was confirmed that the trimeric peptide according to the present invention can pass through the blood-brain barrier (BBB) ​​and act on target cells, microglia. In addition, it was confirmed that the peptide reduces neuroinflammation by inducing microglia from an inflammatory state to an anti-inflammatory state in a disease environment, and increases phagocytic function to induce the removal of amyloid beta protein. In addition, a reduction in amyloid beta was confirmed in an Alzheimer's disease animal model administered the peptide. Therefore, the peptide of the present invention can be usefully utilized as an active ingredient in a composition for the prevention or treatment of degenerative brain diseases.

[0024] Furthermore, the present invention confirmed that synaptic plasticity was restored and cognitive impairments related to anxiety and learning and memory were improved in an Alzheimer's disease animal model administered the trimeric peptide according to the present invention. In addition, it was confirmed that cognitive impairment related to memory was alleviated in an animal model of dementia administered the peptide. Therefore, the peptide of the present invention can be usefully utilized as an effective ingredient in a composition for the prevention or treatment of cognitive impairment, learning impairment, or memory impairment.

[0025] In addition, the trimer-shaped peptide according to the present invention is composed of very small-sized peptides, so that side effects resulting from administration of external substances can be minimized.

[0026] Figure 1 is a schematic diagram illustrating a method for inducing an Alzheimer's disease environment in microglia and treating them with a trimeric peptide KINE-101 manufactured according to one embodiment of the present invention.

[0027] Figure 2 is a diagram confirming a decrease in the expression of the inflammatory state marker CD86 and an increase in the expression of the anti-inflammatory state marker CD206 after treating microglia cultured in an Alzheimer's disease environment with KINE-101 (ns p>0.05; * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001, scale bar: 100 μm).

[0028] Figure 3 is a diagram confirming a decrease in the production of inflammatory substance NO (Nitric oxide) after treating microglial cells cultured in an Alzheimer's disease environment with KINE-101 (ns p>0.05; * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001, scale bar: 100 μm).

[0029] Figure 4 is a diagram showing the intracellular movement of amyloid-beta (Aβ) after treating microglial cells cultured in an Alzheimer's disease environment with KINE-101 (ns p>0.05; * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001, scale bar: 100 μm).

[0030] Figure 5 is a schematic diagram illustrating a method for testing the blood-brain-barrier (BBB) ​​penetration of KINE-101 in a mouse model.

[0031] Figure 6 is a diagram confirming the BBB penetration of KINE-101 in a mouse model.

[0032] Figure 7 is a diagram confirming the reduction of brain amyloid beta by KINE-101 in an Alzheimer's disease mouse model induced by amyloid beta (ns p>0.05; *** p<0.001).

[0033] Figure 8 is a schematic diagram illustrating the method of administering KINE-101 and conducting a behavioral experiment on a mouse model of Alzheimer's disease induced by amyloid beta.

[0034] Figure 9 is a diagram illustrating a method for performing an Elevated-plus maze behavioral experiment using an Alzheimer's disease mouse model induced by amyloid beta.

[0035] Figure 10 is a diagram illustrating a method for performing the Novel Object Recognition Test (NORT) using an Alzheimer's disease mouse model induced by amyloid beta.

[0036] Figure 11 is a diagram illustrating a method for performing an Object Location Test (OLT) using an Alzheimer's disease mouse model induced by amyloid beta.

[0037] Figure 12 shows the results of an Elevated-plus maze behavioral experiment in a mouse model of Alzheimer's disease induced by amyloid beta administered with KINE-101 (* p<0.05; ** p<0.01).

[0038] Figure 13 shows the NORT results of an Alzheimer's disease mouse model induced by amyloid beta administered with KINE-101 (* p<0.05).

[0039] Figure 14 shows the OLT results of an Alzheimer's disease mouse model induced by amyloid beta administered with KINE-101 (* p<0.05).

[0040] Fig. 15 is a diagram showing a method for measuring long-term potentiation (LTP) and the measurement results by administering KINE-101 to a mouse model of Alzheimer's disease induced by amyloid beta. Specifically, Fig. 15A is a diagram schematically showing the hippocampus of a mouse and the mechanism for generating pop-spikes, Fig. 15B is a diagram showing an example of a pop-spike and a method for measuring its amplitude, Fig. 15C is a diagram showing changes in the amplitude of pop-spikes by time zone depending on the administration of KINE-101 in a mouse model of Alzheimer's disease induced by amyloid beta, and Fig. 15D is a diagram showing the recovery of LTP by KINE-101 in a mouse model of Alzheimer's disease induced by amyloid beta (** p<0.01).

[0041] Figure 16 is a diagram showing a method for analyzing Sharp-wave ripples (SWR) by administering KINE-101 to a mouse model of Alzheimer's disease induced by amyloid beta, and the results of the analysis. Specifically, Figure 15A is a diagram showing an example of SWR by frequency, Figure 15B is a diagram confirming an increase in the frequency of SWR occurrence by KINE-101 in a mouse model of Alzheimer's disease induced by amyloid beta, and Figure 15C is a diagram confirming an increase in the intensity of SWR by KINE-101 in a mouse model of Alzheimer's disease induced by amyloid beta (* p<0.05).

[0042] Figure 17 is a diagram showing a method for performing a Y-maze test using a dementia mouse model induced by scopolamine (Figures 17A and 17B) and the test performance results (Figure 17C) (ns p>0.05; * p<0.05; **** p<0.0001; ## p<0.01).

[0043] Hereinafter, the present invention will be described in more detail.

[0044] The present invention provides a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

[0045] In the present invention, the "peptide" refers to a polymer composed of two or more amino acids linked by amide bonds (or peptide bonds). Despite various studies on peptide therapeutics, the peptide itself is too large, and thus has the disadvantage of reducing drug efficacy and causing side effects due to the generation of antibodies and induction of an immune response against the peptide drug itself. Therefore, the present invention is technically significant in that it has identified a peptide in the form of a trimer composed of 10 or fewer amino acids that has pharmaceutically effective activity.

[0046] The peptide of the present invention may be composed of an amino acid represented by SEQ ID NO: 1, and may include an amino acid sequence having a sequence identity of 75% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, with the amino acid sequence represented by SEQ ID NO: 1. More specifically, the peptide of the present invention may include an amino acid sequence having a sequence identity 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%, 99.5% or more with the amino acid sequence represented by SEQ ID NO: 1.

[0047] Additionally, the peptide of the present invention may additionally include a targeting sequence, a tag, a labeled residue, an amino acid sequence manufactured for a specific purpose to increase half-life or peptide stability.

[0048] Additionally, the peptide of the present invention can be obtained using various methods widely known in the art. For example, it can be produced using polynucleotide recombination and protein expression systems, in vitro synthesis through chemical synthesis such as peptide synthesis, and cell-free protein synthesis methods.

[0049] Additionally, a protecting group may be attached to the N- or C-terminus of the peptide to obtain better chemical stability, enhanced pharmacological properties (half-life, absorbability, potency, efficacy, etc.), altered specificity (e.g., broad biological activity spectrum), or reduced antigenicity. Examples of protecting groups include an acetyl group, a fluorenyl methoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, or polyethylene glycol (PEG), but any component that can modify the peptide, particularly enhance the stability of the peptide, may be included without limitation.

[0050] The term "stability" used in the present invention means not only in vivo stability that protects the peptide of the present invention from attack by in vivo protein cleavage enzymes, but also storage stability (e.g., room temperature storage stability).

[0051] The term "polynucleotide" used in the present invention refers to a polymer in which nucleotides are linked and serves to transmit genetic information. For the purposes of the present invention, it may include a sequence that encodes a peptide of SEQ ID NO: 1 and has a sequence homology of at least 75%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% to the polynucleotide sequence encoding the peptide.

[0052] The term "homology" used in the present invention is intended to indicate the degree of similarity with a wild-type amino acid sequence or polynucleotide sequence, and a comparison of such homology can be performed using a comparison program widely known in the art, and the homology between two or more sequences can be calculated as a percentage (%).

[0053] In addition, the present invention provides a pharmaceutical composition for preventing or treating a degenerative brain disease, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating a degenerative brain disease; a use of the peptide or the polynucleotide encoding the same for preparing a pharmaceutical composition for preventing or treating a degenerative brain disease; and a method for treating a degenerative brain disease, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0054] The term “prevention” as used in the present invention means any act of suppressing a disease or delaying its onset by administering a pharmaceutical composition according to the present invention.

[0055] The term "treatment" as used in the present invention means any action in which the symptoms of a disease are improved or beneficially changed by administration of a pharmaceutical composition according to the present invention.

[0056] In the present invention, “subject” means a subject requiring treatment of a disease, and more specifically, means a mammal such as a human or non-human primate, rodent (mouse, rat), dog, cat, horse, or cow.

[0057] In the present invention, the degenerative brain disease may 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 amyloid disease, Dutch amyloidosis, Pick's disease, senile dementia, Lewy Body Dementia, Progressive Supranuclear Palsy, or Frontotemporal Dementia.

[0058] In the present invention, the composition targets microglia and can prevent or treat the degenerative brain disease by targeting microglia and having the following properties:

[0059] i) reducing neuroinflammation by inducing microglia from a pro-inflammatory state to an anti-inflammatory state; and

[0060] ii) Removal of amyloid beta by activating the phagocytosis of microglia.

[0061] Specifically, the composition can prevent or treat the degenerative brain disease by targeting microglia in the brain by passing through the blood-brain-barrier (BBB), inducing the state of inflammatory microglia to an anti-inflammatory state, thereby reducing neuroinflammation, and also increasing phagocytosis to remove amyloid beta, a toxic protein.

[0062] In a specific embodiment of the present invention, the inventors prepared a trimer-type peptide KINE-101 using a PSP fragment (PSP monomer), and confirmed that the KINE-101 targets microglia and induces microglia from an inflammatory state to an anti-inflammatory state, thereby reducing inflammatory substances and increasing phagocytic function, thereby inducing the removal of amyloid beta protein.

[0063] Furthermore, the inventors of the present invention confirmed that KINE-101 reduces amyloid beta in the brain of an Alzheimer's disease mouse model, restores synaptic plasticity, and improves anxiety and cognitive impairments related to learning and memory. Furthermore, they confirmed that KINE-101 alleviates memory-related cognitive impairment in a mouse model of dementia.

[0064] Accordingly, the inventors of the present invention confirmed that the peptide of the present invention targets microglia, activates the phagocytosis of microglia, removes amyloid beta, and induces the state of inflammatory microglia to an anti-inflammatory state, and confirmed the effect of reducing amyloid beta, restoring synaptic plasticity, and improving cognitive impairment related to anxiety and learning and memory in an animal model of degenerative brain disease. Therefore, the peptide of the present invention can be usefully used as an active ingredient of a pharmaceutical composition for preventing or treating degenerative brain disease.

[0065] The peptide of the present invention or the polynucleotide encoding it may be delivered in a pharmaceutically acceptable carrier such as a colloidal suspension, powder, saline solution, lipid, liposome, microspheres, or nano-spheres. They may form a complex with or be associated with a carrier vehicle, and may be delivered in vivo using a carrier system known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances, or fatty acids.

[0066] In addition, pharmaceutically acceptable carriers may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, which are commonly used in formulations. In addition, lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, and the like may be further included in addition to the above ingredients.

[0067] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intramuscularly, intravenously, intraperitoneally, subcutaneously, intradermally, or topically) depending on the intended method, and the dosage varies depending on the patient's condition and body weight, the degree of disease, the drug form, the route of administration, and the time of administration, but can be appropriately selected by those skilled in the art.

[0068] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on the type and severity of the patient's disease, the activity and sensitivity of the drug to the drug, the time of administration, the route of administration and excretion rate, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered simultaneously, separately, or sequentially with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take all of the above factors into consideration and administer an amount that achieves the maximum effect with the minimum amount without causing side effects, and this can be easily determined by those skilled in the art.

[0069] Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, body weight, absorption rate of the active ingredient in the body, inactivation rate, excretion rate, type of disease, and concomitantly administered drugs, and may increase or decrease depending on the route of administration, severity of obesity, sex, body weight, age, etc.

[0070] In addition, the present invention provides a health functional food composition for preventing or improving a degenerative brain disease, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a health functional food composition for preventing or improving a degenerative brain disease; a use of the peptide or the polynucleotide encoding the same for producing a health functional food composition for preventing or improving a degenerative brain disease; and a method for preventing or improving a degenerative brain disease, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0071] As used herein, the term "improvement" means any action that at least reduces a parameter related to the condition being treated, for example, the severity of a symptom.

[0072] In the present invention, the content of the peptide, polynucleotide, and degenerative brain disease is the same as described above, so the specific description is based on the above content, and only the unique composition of the health functional food composition is described below.

[0073] Meanwhile, the inventors of the present invention confirmed that the peptide of the present invention targets microglia, activates the phagocytosis of microglia, removes amyloid beta, and induces the state of inflammatory microglia to an anti-inflammatory state, and confirmed the effect of reducing amyloid beta, restoring synaptic plasticity, and improving cognitive impairment related to anxiety and learning and memory in an animal model of degenerative brain disease. Therefore, the peptide of the present invention can be usefully used as an effective ingredient of a health functional food composition for preventing or improving degenerative brain disease.

[0074] The health functional food composition of the present invention can be used simultaneously with or separately from a drug for treatment before or after the onset of the disease to prevent or improve the disease.

[0075] In the health functional food composition of the present invention, the active ingredient may be added directly to a food or used in combination with other foods or food ingredients, and may be used appropriately according to conventional methods. The amount of the active ingredient may be appropriately determined depending on the intended use (prevention or improvement). Generally, when manufacturing a food or beverage, the composition of the present invention may be added in an amount of preferably 15% by weight or less, more preferably 10% by weight or less, relative to the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range.

[0076] The health functional food composition of the present invention, in addition to containing the above-described effective ingredient, may contain other ingredients as essential ingredients without particular limitation. For example, it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, etc.; and polysaccharides such as dextrin, cyclodextrin, etc., and conventional sugars, and sugar alcohols such as xylitol, sorbitol, erythritol, etc. In addition to the above-described flavoring agents, natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the above-described natural carbohydrates can be appropriately determined by those skilled in the art.

[0077] In addition to the above, the health functional food composition of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination, and the ratio of these additives may also be appropriately selected by those skilled in the art.

[0078] In addition, the present invention provides a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment; a use of the peptide or the polynucleotide encoding the same for preparing a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment; and a method for preventing or treating cognitive impairment, learning disability or memory impairment, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0079] The term "cognitive impairment" used in the present invention refers to an abnormality in cognitive ability related to the method of acquiring, remembering, and using knowledge, and cognitive ability includes cognitive functions such as knowledge, memory, understanding, thinking, problem-solving, critical thinking, and creativity.

[0080] The term "learning disability" as used in the present invention refers to a disability that exhibits significant difficulty in learning functions such as listening, speaking, attention, perception, memory, and problem solving, or in areas of academic achievement such as reading, writing, and mathematics.

[0081] The term "memory impairment" as used in the present invention refers to a state in which one cannot remember newly learned facts, cannot remember the names of objects or people, or has difficulty or is unable to recall past experiences.

[0082] These cognitive impairments, learning disabilities, or memory impairments can be caused by a variety of causes and circumstances, and the present invention does not specifically limit the causes. For example, they may be caused by degenerative brain diseases such as Alzheimer's disease, dementia, mild cognitive impairment, cognitive deficits, and attention deficits.

[0083] In the present invention, the contents of the peptide, polynucleotide, degenerative brain disease, and pharmaceutical composition are the same as those described above, so the specific description refers to the above contents.

[0084] Meanwhile, the inventors of the present invention have confirmed that the peptide of the present invention has the effect of improving synaptic plasticity recovery, anxiety, and cognitive impairment related to learning and memory in an animal model of a degenerative brain disease, and therefore, the peptide of the present invention can be usefully used as an active ingredient of a pharmaceutical composition for preventing or treating cognitive impairment, learning impairment, or memory impairment.

[0085] In addition, the present invention provides a health functional food composition for enhancing cognitive ability, learning ability or memory, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same; a use of the peptide or the polynucleotide encoding the same for use as a health functional food composition for enhancing cognitive ability, learning ability or memory; a use of the peptide or the polynucleotide encoding the same for manufacturing a health functional food composition for enhancing cognitive ability, learning ability or memory; and a method for enhancing cognitive ability, learning ability or memory, comprising administering to a subject the peptide or the polynucleotide encoding the same.

[0086] In the present invention, the contents of the peptide, polynucleotide, degenerative brain disease, and health functional food composition are the same as those described above, so the specific description refers to the above contents.

[0087] Meanwhile, the inventors of the present invention have confirmed that the peptide of the present invention has the effect of improving synaptic plasticity recovery, anxiety, and cognitive impairment related to learning and memory in an animal model of a degenerative brain disease, and therefore, the peptide of the present invention can be usefully used as an effective ingredient of a health functional food composition for enhancing cognitive ability, learning ability, or memory.

[0088] Hereinafter, the present invention will be described in detail by examples.

[0089] However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0090] <Example 1> Production of peptides

[0091] In this example, a trimer-type polymer KINE-101 was prepared using a PSP fragment (PSP monomer) as shown in [Table 1] below. Subsequently, the synthesized peptide was purified using high-performance liquid chromatography (SHIMADZU Prominence HPLC), and the column used was a Shiseido capcell pak C18 Column (4.6 x 50 mm). In addition, the mass of the synthesized peptide was confirmed using a mass spectrometer (AXIMA Assurance, MALDI-TOF, Shimadzu).

[0092] Peptide name Amino acid sequence Molecular weight (MW) KINE-101PSPPSPPSP (SEQ ID NO: 1) 861.9 g / mol

[0093] <Example 2> Confirmation of increased anti-inflammatory and phagocytic functions of microglia by KINE-101 in an Alzheimer's disease setting.

[0094] Microglia, which remove various foreign substances, including amyloid-beta, through phagocytosis, are also known to be involved in neurodegenerative diseases through chronic inflammation and excessive activation of synaptic pruning. Therefore, the effects of KINE-101 were confirmed by targeting microglia cultured in an Alzheimer's disease environment.

[0095] Specifically, as shown in the schematic diagram of Fig. 1, 1 μM of oligomeric amyloid beta protein (Aβ), known as the cause of Alzheimer's disease, and 10 ng / mL of interferon-gamma (INFγ), an inflammatory substance, were treated to cultured human microglial cells (hMG) to create an environment conducive to Alzheimer's disease, the biggest cause of dementia. Under these conditions, KINE-101, manufactured in <Example 1>, was treated at 1, 5, 10, 100, or 500 ng / mL. After two days, the culture medium was changed and the same drug was treated again.

[0096] To investigate whether the state of microglia was induced from pro-inflammatory (M1) to anti-inflammatory (M2) after two days, cells were fixed using a fixative, labeled with antibodies against CD86, a marker of inflammatory state of microglia, and CD206, a marker of anti-inflammatory state, and stained with a fluorescently labeled secondary antibody. Images were obtained under a fluorescence microscope, and the fluorescence signals were quantified using a software program to compare the degree of change from a pro-inflammatory state to an anti-inflammatory state induced by KINE-101 (Fig. 2).

[0097] Furthermore, to evaluate the reduction of inflammatory substances by KINE-101, nitric oxide (NO), an intracellular inflammatory substance that is significantly involved in the progression of Alzheimer's disease, was stained with difluorofluorescein-FM diacetate, and images were obtained using a fluorescence microscope. The intensity of the fluorescence signal was quantified using a software program, and the degree of NO reduction by KINE-101 was confirmed (Fig. 3).

[0098] In addition, to investigate the degree of increased microglial phagocytosis by KINE-101, amyloid beta protein translocated into the cells was quantified. Amyloid beta protein is labeled with a pH-sensitive red fluorescent substance, and has the characteristic of fluorescence emitting due to the low pH (pH 3-5) of the lysosome when it translocates to the lysosome, an intracellular organelle that plays a role in protein degradation. Therefore, the fact that red fluorescence is emitted within the cell means that amyloid beta is being degraded in the lysosome after translocating into microglia by phagocytosis. Red fluorescence images were obtained using a fluorescence microscope, and quantified and compared using a software program (Fig. 4).

[0099] As a result, as shown in Fig. 2, CD86, an inflammatory state marker, was decreased in microglia cultured in an Alzheimer's disease environment in a concentration-dependent manner by KINE-101, whereas CD206, an anti-inflammatory state marker, was increased. These results imply that KINE-101 has the function of inducing the state of microglia existing in an inflammatory state in a degenerative brain disease environment to an anti-inflammatory state.

[0100] Furthermore, as shown in Figure 3, KINE-101 concentration-dependently reduced NO, an inflammatory substance produced in microglia cultured in an Alzheimer's disease environment. These results suggest that KINE-101 possesses anti-inflammatory properties that reduce inflammatory substances in microglia that are increased in degenerative brain disease environments.

[0101] Furthermore, as shown in Figure 4, the intracellular transport of amyloid beta in microglia cultured in an Alzheimer's disease environment increased in a concentration-dependent manner with KINE-101. These results indicate that KINE-101 has the ability to increase microglia phagocytosis.

[0102] The above results show that KINE-101 targets microglia that exist in an inflammatory state in the Alzheimer's disease environment, inducing them into an anti-inflammatory state, thereby reducing inflammatory substances and increasing phagocytic function, thereby inducing the removal of amyloid beta protein.

[0103] <Example 3> Confirmation of blood-brain barrier penetration by KINE-101 in an animal model

[0104] In the treatment of neurodegenerative diseases, the blood-brain barrier (BBB) ​​acts as a barrier to drug entry. Due to the structural specificity of brain capillaries, the BBB prevents most drugs from reaching target cells. Therefore, to determine whether KINE-101 can cross the BBB and act on target cells in neurodegenerative diseases, we administered KINE-101 to a mouse model and examined BBB penetration.

[0105] Specifically, as shown in the schematic diagram of Fig. 5, 20 mg / kg of KINE-101 labeled with fluorescence (FITC) was intravenously injected into the tail of 8-week-old male C57BL / 6 mice, and then the fluorescence signal measured in the brain at different time points was observed using bioimaging equipment (Fig. 6).

[0106] As a result, as shown in Fig. 6, a fluorescent signal was observed in the brain 10 seconds after KINE-101 administration, and the strongest signal was confirmed 10 minutes later. In addition, the fluorescent signal persisted for 2 hours.

[0107] Based on the above results, it is expected that KINE-101 can pass through the BBB, and based on the in vitro experimental results confirmed above, KINE-101 that passes through the BBB can induce microglia in the brain to an anti-inflammatory state, thereby reducing inflammatory substances and increasing phagocytic function, thereby inducing the removal of amyloid beta protein.

[0108] <Example 4> Confirmation of the efficacy of KINE-101 in an animal model of degenerative brain disease.

[0109] <4-1> Confirmation of reduction in amyloid beta protein by KINE-101 in an Alzheimer's disease mouse model

[0110] To investigate the effect of KINE-101 on degenerative brain diseases, KINE-101 was administered to a mouse model of Alzheimer's disease induced by amyloid beta, and changes in the expression of amyloid beta were confirmed.

[0111] Specifically, the 5xFAD mouse, an Alzheimer's disease mouse model induced by amyloid beta, was provided by the Jackson Laboratory. The Alzheimer's disease mouse model is known to overexpress human amyloid beta protein, oligomerize outside the cell, and eventually precipitate into insoluble protein clumps, damaging nerve cells and causing dementia. Accordingly, KINE-101, synthesized in <Example 1>, was administered twice a week at 50 or 100 mg / kg via intravenous injection into the tail of 4-month-old 5xFAD mice induced by amyloid beta. Four weeks later, the brain tissue of the mouse was thinly sliced ​​using a vibratome, and amyloid beta protein was probed using an antibody with fluorescent (FITC) dye, and images were obtained using a fluorescence microscope (Fig. 7A), and the amount of amyloid beta protein deposited in the brain tissue was quantified by analyzing it using Cytation5 software (Fig. 7B).

[0112] As a result, as shown in Figure 7, in the case of 5xFAD mice, a significant amount of precipitated amyloid beta protein was observed throughout the brain tissue. In contrast, amyloid beta protein was somewhat reduced in the brain tissue of mice administered 50 mg / kg of KINE-101. In the group administered 100 mg / kg of KINE-101, which was twice the concentration, it was confirmed that amyloid beta protein was reduced by approximately 60% or more in the brain tissue.

[0113] These results demonstrate that KINE-101 can cross the BBB and remove toxic proteins deposited in the brain. In particular, considering the increased uptake of amyloid-beta protein by microglia by KINE-101, the reduction in amyloid-beta protein in the mouse brain is likely due to phagocytosis by microglia activated by KINE-101.

[0114] <4-2> Confirmation of behavioral improvement by KINE-101 in an Alzheimer's disease mouse model

[0115] To investigate the effects of KINE-101 on anxiety, learning, and memory impairment induced by degenerative brain diseases, we administered KINE-101 to a mouse model of Alzheimer's disease induced by amyloid beta and observed behavioral changes.

[0116] Specifically, as shown in the schematic diagram of Fig. 8, 4-month-old 5xFAD mice induced by amyloid beta were subcutaneously injected with saline or 100 mg / kg of KINE-101 synthesized in <Example 1> twice a week for a total of 2 months. In addition, normal mice born in the same litter as the 5xFAD mice were used as a normal control group, and were subcutaneously injected with saline in the same manner as above.

[0117] After administration, an elevated plus maze behavioral test was conducted to evaluate the presence of anxiety disorder behaviors using a cross-shaped elevated maze, as shown in Figure 9. The elevated plus maze equipment used in this experiment was designed to be 40 cm above the floor, and of the four spaces (arms), two facing each other were closed spaces with walls (closed arms), and the remaining two were open spaces (open arms) without walls. This behavioral test, which utilizes the natural characteristic of chordates to avoid elevated spaces without any protective devices due to the threat of falling, can determine whether the experimental animals have anxiety disorders based on the time spent in an open space where they feel threatened, compared to a closed space where they feel relatively safe. Compared to the normal control group in the experiment, if the preference for open spaces is extremely low, it can be judged as a hyper-anxiety model, and if the preference for open spaces is high, it can be judged as an anxiety-insensitive disorder (Hypo-anxiety). It is known that animal models of Alzheimer's disease show anxiety-insensitive patterns. This is reported to be a behavior resulting from the joint action of the cerebrum, amygdala, and hippocampus, which are responsible for threat recognition and risk assessment. Before the behavioral experiment, the experimental animals that had undergone a habituation process for at least 1 hour in the experimental space were allowed to explore freely in the maze sequentially without any disturbance. After recording the space in which the experimental animals stayed longer for 5 minutes through video recording, the time spent in the open space without any protective barrier was compared to quantitatively compare the presence or absence of anxious behavior in the target animals (Fig. 12).

[0118] In addition, to investigate whether KINE-101 can improve cognitive impairment related to memory, we conducted the Novel Object Recognition Test (NORT), which tests memory for objects. NORT is a test method that utilizes the habit of curious laboratory animals to be more interested in novel objects and spend more time exploring them. As shown in Figure 10, two objects were installed in the test space and the laboratory animals were allowed to explore them to induce memory formation. Then, one of the objects was replaced with a new object and the time the laboratory animals spent remembering the old object and exploring the new object was measured. In addition, the discrimination index was calculated using the following mathematical formula (Figure 13): Discrimination Index = Novel Object Exploration Time / (New Object Exploration Time + Previous Object Exploration Time).

[0119] In addition, the Object Location Test (OLT) was performed to determine whether spatial memory, a representative cognitive impairment in Alzheimer's patients, was improved. Like the NORT, the OLT has the experimental animals explore two objects, but instead of replacing them with new objects, as shown in Figure 11, only the locations of the existing objects are changed. This is a test method to observe whether the exploration time for the new space increases by inducing the reorganization of spatial memory cells (place cells) in the hippocampus due to the moving objects in the curious experimental animals. The discrimination index was calculated using the following mathematical formula (Figure 14): Discrimination Index = Exploration time in the space where the object moved / (Exploration time in the space where the object moved + Exploration time in the space where the object did not move).

[0120] As a result, as shown in Fig. 12, the results of the evaluation of anxiety disorder behavior showed that the KINE-101 administration group [5xFAD (KINE-101)] spent significantly less time in an open space than the Alzheimer's disease-induced group [5xFAD (Vehicle)], and this was confirmed to be at a similar level to the normal control group [Veh-Littermate control (Vehicle)].

[0121] Furthermore, as shown in Figure 13, the KINE-101-administered group [5xFAD (KINE-101)] spent more time exploring novel objects than the Alzheimer's disease-induced group [5xFAD (Vehicle)] over a two-month period of NORT. These results suggest that KINE-101 administration helps restore memory impairment for objects.

[0122] Furthermore, as shown in Figure 14, the KINE-101-administered group [5xFAD (KINE-101)] spent more time exploring the new space where objects had been moved compared to the Alzheimer's disease-induced group [5xFAD (Vehicle)] after 2 months of OLT. These results suggest that KINE-101 administration helps restore spatial memory impairment.

[0123] The above results show that KINE-101 effectively improves anxiety and cognitive impairment related to learning and memory that appear in degenerative brain diseases such as Alzheimer's disease.

[0124] <4-3> Confirmation of increased synaptic plasticity and subsequent recovery of cognitive function by KINE-101 in an Alzheimer's disease mouse model

[0125] The transition from short-term to long-term memory in the creation of episodic memory requires the activity of the hippocampus, a region of the brain, and synaptic plasticity, a representative memory mechanism of the hippocampus. In particular, synaptic plasticity is known to be a key mechanism for learning and memory formation, as information transmission between neurons, the basic units of the brain, occurs. Therefore, to investigate the effect of KINE-101 on memory impairment caused by degenerative brain diseases, we administered KINE-101 to a mouse model of Alzheimer's disease induced by amyloid beta and examined whether synaptic plasticity was restored.

[0126] Specifically, using the mouse model of the above Example <4-2>, long-term potentiation (LTP) was measured through electrophysiological analysis. LTP was determined by comparing the pop-spike amplitude before (Baseline) and 25 minutes after applying the short-term high-frequency stimulation, theta burst stimulation (TBS). To measure LTP, mice were anesthetized, and an electrical signal, a population-spike (pop-spike), was generated in the hippocampus of the anesthetized mice (Fig. 15).

[0127] In addition, the replay mechanism by which spatial memory cells are strengthened to be converted into long-term memory is observed in the form of sequential burst activation of hippocampal neurons when the experimental animal stops exploring. This phenomenon is called Sharp-wave (1-50 Hz) and ripples (125-250 Hz) depending on the signal type, and is collectively expressed as SWR (Sharp-wave ripples). In order to determine whether the ability to create spatial memory is restored in an Alzheimer's disease mouse model by administering KINE-101, the occurrence frequency and intensity of SWR were compared and analyzed. SWR is the frequency (Event / s) and intensity (uV) when a signal of a set frequency (Sharp wave: 1-50 Hz, Ripples: 125-250 Hz) exceeds the threshold (4 times the standard deviation) after measuring continuous electrophysiological signals through electrodes implanted in the hippocampus. 2 ) was measured and obtained (Fig. 16).

[0128] As a result, as shown in Fig. 15, the LTP measurement results showed that LTP decreased in the Alzheimer's disease-induced group [5xFAD (Vehicle)] compared to the normal control group [Wild-Littermate control (Vehicle)], whereas LTP increased in the KINE-101-administered group [5xFAD (KINE-101)] compared to the Alzheimer's disease-induced group. These results indicate that KINE-101 restores LTP and thus synaptic plasticity is restored.

[0129] In addition, as shown in Figure 16, the SWR analysis results confirmed that the frequency and intensity of SWR were increased in the KINE-101-administered group [5xFAD (KINE-101)] compared to the Alzheimer's disease-induced group [5xFAD (Vehicle)]. These results suggest that KINE-101 contributed to the recovery of SWR, which indicates the activity of spatial memory cells.

[0130] The above results suggest that KINE-101 helps improve memory for objects and spaces in degenerative brain diseases such as Alzheimer's disease by restoring synaptic plasticity in the hippocampus and promoting the formation mechanism of spatial memory cells.

[0131] <4-4> Confirming the effectiveness of KINE-101 in a dementia mouse model

[0132] To investigate the effect of KINE-101 on learning and memory impairment caused by dementia due to degenerative brain disease, mice were administered KINE-101 and scopolamine to induce dementia, and then the Y-maze test was performed.

[0133] Specifically, scopolamine is a competitor that interferes with the binding of the neurotransmitter acetylcholine to acetylcholine receptors expressed on neurons, and is known to induce cognitive impairments, including learning and memory, when administered to animals. In particular, scopolamine is known to damage neurons by activating microglia, increasing inflammatory cytokines and oxidative stress. In addition, the Y-maze test is a behavioral experiment designed to test the working memory of animals, considering the high affinity of mice to show curiosity about novel places (Figure 17A). Accordingly, as shown in the schematic diagram in Figure 17B, 8-week-old male C57BL / 6 mice were divided into four groups, and KINE-101 (experimental group) or PBS (negative control group) was administered subcutaneously to each group twice a week for two weeks under the conditions shown in Table 2 below, and then scopolamine was administered intraperitoneally four days later. Thirty minutes after scopolamine administration, mice were placed in a Y-maze, and the order in which they moved through each passage for 5 minutes was recorded. The number of times they moved through different passages was converted to quantify the spontaneous alternation rate (% Alternation) (Fig. 17C).

[0134] Group Administration Substance (Administration Method)ControlPBS(SC)Vehicle(PBS)PBS(SC) + Scopolamine(IP, 1 mg / kg)KINE-101, 50mg / kgKINE-101 50 mg / kg(SC) + Scopolamine(IP, 1 mg / kg)KINE-101, 100mg / kgKINE-101 100 mg / kg(SC) + Scopolamine(IP, 1 mg / kg)

[0135] As a result, as shown in Fig. 17, in the case of the group of mice administered scopolamine [Vehicle (PBS)], the proportion of moving to the same passage was high, so the spontaneous alternation rate was low, whereas in the case of the positive control group [Control], the proportion of moving to a new passage was high. In the case of the group of mice administered KINE-101 [KINE-101], the spontaneous alternation rate was statistically significantly high, and a concentration-dependent trend was confirmed. In particular, the group of mice administered 100 mg / kg of KINE-101 [KINE-101, 100 mg / kg] had a similar spontaneous alternation rate to the positive control group. Meanwhile, the total number of passages moved was similar regardless of drug administration, which means that the drug did not affect the motor nerves of the mice, and the above results were not artifacts due to changes in the motor nerves of the mice. These results indicate that KINE-101 can alleviate the impairment of learning and memory ability induced by neuronal damage in an inflammatory and oxidative stress environment induced by scopolamine, and that KINE-101 can also exert the same effect and alleviate the impairment of cognitive ability in other dementia-causing degenerative brain diseases that contain similar etiological environments.

[0136] The peptide of the present invention targets microglia, thereby reducing neuroinflammation by inducing the state of inflammatory microglia to an anti-inflammatory state in a disease environment, and exhibits the effect of removing amyloid beta protein by increasing phagocytic function, and exhibits the effect of reducing amyloid beta, restoring synaptic plasticity, and improving cognitive impairment related to anxiety and learning and memory in an animal model of a degenerative brain disease, and therefore can be usefully used as an active ingredient of a composition for preventing or treating a degenerative brain disease, cognitive impairment, learning disability, or memory impairment resulting therefrom.

Claims

1. A pharmaceutical composition for preventing or treating a degenerative brain disease, comprising as an active ingredient a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

2. A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the N- or C-terminus of the peptide in paragraph 1 is bonded to a protecting group selected from the group consisting of an acetyl group, a fluorenyl methoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, and polyethylene glycol (PEG).

3. A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the degenerative brain disease in claim 1 is selected from the group consisting of dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, cerebral amyloid angiopathy, amyloid stroke, systemic amyloid disease, Dutch amyloidosis, Pick's disease, senile dementia, Lewy Body Dementia, progressive supranuclear palsy, and frontotemporal dementia.

4. A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the composition according to claim 1 passes through the blood-brain barrier.

5. A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the composition targets microglial cells in the first paragraph.

6. In the fifth paragraph, the composition is a pharmaceutical composition for preventing or treating a degenerative brain disease, which targets microglial cells and has the following properties: i) reducing neuroinflammation by inducing microglia from a pro-inflammatory state to an anti-inflammatory state; and ii) Removal of amyloid beta by activating the phagocytosis of microglia.

7. A pharmaceutical composition for preventing or treating a degenerative brain disease, wherein the composition is formulated for oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, intradermal administration, or topical administration in accordance with paragraph 1.

8. A health functional food composition for preventing or improving degenerative brain diseases, comprising as an active ingredient a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

9. A pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment, comprising as an active ingredient a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

10. A health functional food composition for enhancing cognitive ability, learning ability or memory, comprising as an active ingredient a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

11. A method for treating a degenerative brain disease, comprising administering to a subject a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

12. A method for preventing or improving a degenerative brain disease, comprising administering to a subject a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

13. A method for preventing or treating cognitive impairment, learning disability, or memory impairment, comprising administering to a subject a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

14. A method for enhancing cognitive ability, learning ability, or memory, comprising administering to a subject a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same.

15. Use of a peptide consisting of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating degenerative brain diseases.

16. Use of a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for use as a health functional food composition for preventing or improving degenerative brain diseases.

17. Use of a peptide comprising an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same for use as a pharmaceutical composition for preventing or treating cognitive impairment, learning disability or memory impairment.

18. Use of a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for use as a health functional food composition for enhancing cognitive ability, learning ability or memory.

19. Use of a peptide consisting of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for manufacturing a pharmaceutical composition for preventing or treating a degenerative brain disease.

20. Use of a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for manufacturing a health functional food composition for preventing or improving degenerative brain diseases.

21. Use of a peptide comprising an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same for the manufacture of a pharmaceutical composition for the prevention or treatment of cognitive impairment, learning disability or memory impairment.

22. Use of a peptide composed of an amino acid represented by sequence number 1 or a polynucleotide encoding the same for manufacturing a health functional food composition for enhancing cognitive ability, learning ability or memory.

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