WO2023120408A1 - Composition for suppressing or ameliorating cognitive function decline - Google Patents

Composition for suppressing or ameliorating cognitive function decline Download PDF

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Publication number
WO2023120408A1
WO2023120408A1 PCT/JP2022/046369 JP2022046369W WO2023120408A1 WO 2023120408 A1 WO2023120408 A1 WO 2023120408A1 JP 2022046369 W JP2022046369 W JP 2022046369W WO 2023120408 A1 WO2023120408 A1 WO 2023120408A1
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Prior art keywords
composition
cognitive function
memory
leu
cyclo
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PCT/JP2022/046369
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French (fr)
Japanese (ja)
Inventor
翔太 野中
義 古元
嘉宏 中尾
シャンメイ ヨン
シャージャン リン
グレース カー ヤン チャン
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サントリーホールディングス株式会社
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Publication of WO2023120408A1 publication Critical patent/WO2023120408A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides

Definitions

  • the present invention relates to a composition for suppressing or improving cognitive function, and the like.
  • Patent Document 1 discloses an agent for suppressing and/or improving cognitive function deterioration containing Cyclo (Gly-Pro). It is disclosed that reduction in attention/concentration, language ability, visuospatial/constructive ability is suppressed and/or improved by oral ingestion of this agent for suppressing and/or improving cognitive function decline.
  • Patent Document 1 a component for suppressing the decline of cognitive function or improving cognitive function has been searched for, and disclosed in Patent Document 1, but it is possible to suppress the decline of cognitive function or improve cognitive function. different ingredients are required.
  • the present invention has been made in view of the above-mentioned current situation, and an object of the present invention is to provide a composition for suppressing or improving cognitive function decline.
  • the present invention relates to, but is not limited to, the following composition for suppressing or improving cognitive function.
  • a composition for suppressing or improving cognitive function comprising Cyclo(Leu-Glu) or a salt thereof as an active ingredient.
  • the composition of [1] above which suppresses the production and/or accumulation of amyloid ⁇ .
  • the composition of [1] or [2] above which suppresses the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • composition "enhances cognitive function”, “suppresses deterioration of cognitive function”, “maintains good cognitive function”, “improves memory”, “suppresses deterioration of memory”, “improves memory “maintaining good memory”, “improving memory accuracy”, “preventing memory impairment”, “improving memory impairment”, “maintaining memory as a part of cognitive function”, and “preventing memory loss” functions that are suitable for people to become,””improve memory accuracy and judgment accuracy, which are part of cognitive function", “improve memory retention or consolidation”, “maintain enhanced cognitive function”, “improves executive function”, “promotes attention and concentration”, “improves learning ability”, “maintains and improves orientation”, “delays age-related cognitive decline", “ labeled with one or more functions selected from the group consisting of "strengthening short-term and long-term memory”, “promoting verbal and visuospatial memory” and “maintaining/improving logical thinking ability”
  • the composition according to any one
  • composition for suppressing or improving cognitive function can be provided.
  • the composition of the present invention can be used as food, beverages, pharmaceuticals, etc. for suppressing or improving cognitive function.
  • FIG. 1 shows the ⁇ -secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo (Leu-Ala) (Comparative Example 1) and (Cyclo (Leu-Glu) (Examples 1 and 2). graph.
  • composition for suppressing or improving cognitive function decline of the present invention contains Cyclo(Leu-Glu) or a salt thereof.
  • the composition for suppressing or improving cognitive function decline of the present invention contains Cyclo (Leu-Glu) or a salt thereof as an active ingredient.
  • the composition for suppressing or improving cognitive function deterioration of the present invention may be referred to as the composition of the present invention.
  • the composition of the present invention is used for suppressing deterioration of cognitive function or improving cognitive function.
  • Cyclo(Leu-Glu) (cycloleucylglutamate) used in the present invention is a cyclic dipeptide having a structure in which leucine and glutamic acid are condensed.
  • the term "cyclic dipeptide” is characterized by having amino acids as constituent units, and is a diketopiperazine structure produced by dehydration condensation between the amino group of the N-terminal side amino acid and the carboxyl group of the C-terminal side amino acid.
  • Cyclo (Leu-Glu) and Cyclo (Glu-Leu) represents the same cyclic dipeptide.
  • the salt of Cyclo(Leu-Glu) is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for food and drink, and may be either an acid salt or a basic salt.
  • Acid salts include, for example, inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates; Examples include organic acid salts such as acid salts and propionate salts.
  • basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
  • Cyclo(Leu-Glu) and salts thereof are not particularly limited. Cyclo(Leu-Glu) or a salt thereof can be produced according to a known method. Cyclo(Leu-Glu) and its salts may be derived from natural products, may be artificially synthesized, may be produced by an enzymatic method or a microbial fermentation method, may be linear It may be synthesized by dehydrating and cyclizing the dipeptide. For example, protein hydrolysates, such as collagen hydrolysates, can be heated to yield heat-treated peptides rich in cyclic dipeptides, such as Cyclo (Leu-Glu).
  • Cyclo(Leu-Glu) or a salt thereof may be incorporated into the composition using a protein hydrolyzate containing it or a heat-treated product thereof, or a concentrate, dry powder of the protein hydrolyzate or heat-treated product thereof. Or you may mix
  • the composition of the present invention contains, for example, a protein hydrolyzate or heat-treated product thereof, and Cyclo(Leu-Glu) or a salt thereof may be part of the protein hydrolyzate or heat-treated product thereof. Cyclo (Leu-Glu) and salts thereof can also be used as commercially available products.
  • Cyclo(Leu-Glu) has a ⁇ -secretase inhibitory effect, as shown in the examples below.
  • ⁇ -secretase is the enzyme involved in the production of amyloid ⁇ (A ⁇ ).
  • Amyloid- ⁇ is a peptide sometimes referred to as amyloid- ⁇ protein, amyloid- ⁇ peptide or ⁇ -amyloid.
  • Amyloid ⁇ is usually a peptide consisting of around 40 amino acids, and includes amyloid ⁇ 1-42 , amyloid ⁇ 1-40 and the like. Unassociated amyloid- ⁇ is sometimes referred to as amyloid- ⁇ monomer. When amyloid ⁇ aggregates to oligomerize or fibrillate, it exhibits neuronal toxicity.
  • aggregated amyloid ⁇ accumulates without being discharged from the brain, and is considered to trigger the onset of Alzheimer's disease (Alzheimer's dementia). Therefore, suppression of the production and/or accumulation of amyloid ⁇ is effective in preventing Alzheimer's disease or in suppressing progression of the disease, and in suppressing or improving cognitive function.
  • Amyloid ⁇ is produced by the two-step cleavage of amyloid ⁇ precursor protein (APP) by ⁇ -secretase and ⁇ -secretase.
  • APP amyloid ⁇ precursor protein
  • ⁇ -Secretase is the rate-limiting enzyme for amyloid ⁇ production, and its cleavage regulates the total amyloid ⁇ production. Therefore, by inhibiting ⁇ -secretase, the production of amyloid ⁇ can be suppressed, and the accumulation of amyloid ⁇ can be suppressed.
  • composition of the present invention is useful for suppressing the production and/or accumulation of amyloid ⁇ .
  • the composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • the composition of the present invention can be used to suppress deterioration of cognitive function or improve cognitive function by suppressing the production and/or accumulation of amyloid ⁇ .
  • Amyloid ⁇ in the present invention includes non-aggregated amyloid ⁇ and amyloid ⁇ forming aggregates such as oligomers. Aggregates include soluble aggregates (amyloid ⁇ oligomers) in which 2 or more (eg, 2 to 50) amyloid ⁇ aggregates.
  • the cognitive function means brain functions such as memory function, matching function, integration function, executive function, attention (attentive function), and concentration.
  • suppression of decline in cognitive function includes maintenance of cognitive function, delay in progression of decline in cognitive function, and halting decline in cognitive function.
  • Improvement of cognitive function includes improvement of cognitive impairment (eg, reduction (mitigation) of degree of cognitive impairment), recovery of cognitive function, enhancement of cognitive function, and the like.
  • Cognitive impairment means failure of some or all of the above cognitive functions.
  • Suppression or improvement of cognitive function decline includes suppression or improvement of some cognitive function decline.
  • Recovering includes recovering at least partially.
  • the causes of cognitive decline and cognitive dysfunction include aging, neurodegenerative diseases such as Alzheimer's disease, Pick's disease, and diffuse Lewy body disease, cerebral infarction, cerebral hemorrhage, chronic subdural hematoma, brain tumor, and encephalitis. ⁇ Cerebral diseases such as normal pressure hydrocephalus, Creutzfeldt-Jakob disease, etc.
  • a composition containing Cyclo(Leu-Glu) or a salt thereof is suitably used for suppressing deterioration of cognitive function due to Alzheimer's disease and improving cognitive impairment due to Alzheimer's disease.
  • the age-related cognitive impairment may be age-related cognitive impairment in middle-aged and elderly individuals. Middle-aged and elderly people include elderly people.
  • the composition containing Cyclo (Leu-Glu) or a salt thereof is used for suppressing or improving at least one cognitive function selected from the group consisting of memory function, executive function, attention and concentration. preferably used.
  • the composition of the present invention for example, suppresses the deterioration of at least one cognitive function selected from the group consisting of memory function, executive function, attention and concentration due to Alzheimer's disease, or improves the above cognitive function that has been deteriorated due to Alzheimer's disease. can be used to
  • the memory function is the ability to retain past experiences and use them later by reproducing them.
  • the memory functions are classified into, for example, verbal memory functions, non-verbal memory functions, visuospatial memory functions, gist memory functions, working memory functions, and the like.
  • the executive function is the ability to act systematically in order to achieve a goal, and is a very important function for humans to carry out social, independent, and creative activities.
  • Executive functions are coordinated in the frontal lobe by combining various information such as visual, auditory, and olfactory information with past experiences.
  • composition of the present invention is preferably used for suppressing or improving memory function deterioration, and is useful for improving verbal memory function, non-verbal memory function, visuospatial memory function, gist memory function and working memory function. It is more preferably used for suppression of deterioration or improvement.
  • the composition of the present invention can be used, for example, for the prevention or amelioration of conditions or diseases exhibiting cognitive decline, conditions or diseases associated with accumulation of amyloid ⁇ in the brain.
  • Such conditions or diseases include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
  • the composition of the present invention can be used to prevent or ameliorate the above conditions or diseases, and can be preferably used for the prevention of the above conditions or diseases.
  • prevention of a condition or disease includes preventing onset, delaying onset, reducing the rate of onset, reducing risk of onset, and the like.
  • Ameliorating a condition or disease includes ameliorating the subject from the condition or disease, alleviating symptoms of the condition or disease, ameliorating symptoms of the condition or disease, slowing progression of the condition or disease, preventing the condition or disease. etc.
  • Cognitive function is known to decline in Alzheimer's disease and mild cognitive impairment.
  • Symptoms of cognitive decline in Alzheimer's disease and mild cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficult to name things), apraxia, agnosia (walking in familiar places). (e.g., getting lost), decreased orientation (the ability to correctly recognize one's own situation, such as place, time, name of person, etc.), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, executive function executive dysfunction (inability to plan and do things), decreased ability to concentrate, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, decreased information processing speed, etc.
  • the composition of the present invention can be used, for example, for prevention or amelioration of the above symptoms.
  • compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use).
  • Non-therapeutic is a concept that does not involve medical intervention, i.e. human surgery, treatment or diagnosis.
  • the composition for suppressing or improving cognitive function decline of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
  • the agent itself can be provided as a composition, or a composition containing the agent can be provided.
  • the composition for suppressing or improving cognitive function decline of the present invention can also be said to be an agent for suppressing or improving cognitive function decline.
  • compositions of the invention may be either oral or parenteral.
  • the compositions of the invention are preferably oral compositions.
  • the composition of the present invention can be in the form of, for example, foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. Foods, beverages, or pharmaceuticals are preferred.
  • the composition of the present invention can also be used by adding it to foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like.
  • the form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granule, tablet, etc.), liquid, paste, or the like.
  • composition of the present invention contains Cyclo (Leu-Glu) or a salt thereof, and further contains various diluents, acidulants, antioxidants, stabilizers, preservatives, etc. that are acceptable as additives for foods, beverages, pharmaceuticals, etc.
  • Ingredients, flavors, emulsifiers, pigments, seasonings, pH adjusters, nutritional enhancers, and the like may be added.
  • composition of the present invention when used as a food or drink, Cyclo (Leu-Glu) or a salt thereof may be added to ingredients that can be used for food or drink (e.g., food materials, food additives used as necessary). can be blended to make various food and drink products.
  • Food and drink are not particularly limited, and examples thereof include general food and drink, health food, food with function claims, food for specified health use, health supplement, and food for the sick.
  • Health foods, foods with function claims, foods for specified health uses, health supplements, etc. are various formulations such as liquids, fine granules, tablets, granules, powders, capsules, chewable formulations, dry syrups, and liquid diets. Can be used as a form.
  • composition of the present invention When the composition of the present invention is used as a drug or quasi-drug, Cyclo (Leu-Glu) or a salt thereof is blended with a pharmacologically acceptable carrier, an optional additive, etc. , various dosage forms of pharmaceuticals or quasi-drugs.
  • Such carriers, additives, etc. may be those that can be used for pharmaceuticals or quasi-drugs and are pharmacologically acceptable.
  • antioxidants, coloring agents and the like can be mentioned.
  • administration (ingestion) forms of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, enteral, injection, etc.) forms of administration.
  • composition of the present invention When the composition of the present invention is used as a drug or quasi-drug, it is preferably an oral drug or oral quasi-drug.
  • Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, dragees, capsules, suspensions, emulsions, chewables and the like.
  • Dosage forms for parenteral administration include, for example, injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants) and the like.
  • the pharmaceutical may be a non-human veterinary pharmaceutical.
  • Cyclo (Leu-Glu) or a salt thereof may be added to the feed.
  • Feed also includes feed additives. Examples of feeds include livestock feeds for cows, pigs, chickens, sheep, horses, etc.; small animal feeds for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.;
  • the composition of the present invention when used as a food or drink, a drug, a quasi-drug, a feed, etc., the production method is not particularly limited, and Cyclo (Leu-Glu) or a salt thereof may be used to prepare a general It can be manufactured by a method.
  • the composition of the present invention is preferably a liquid composition, more preferably a beverage.
  • the beverage may be, for example, a functional beverage.
  • the form of the beverage is not particularly limited, and may be a packaged beverage.
  • Containers for packaged beverages are not particularly limited, and containers of any shape and material may be used. For example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; Containers; glass containers such as glass bottles; and wooden containers such as barrels. Any of commonly used containers can be used.
  • a packaged beverage is obtained by filling and sealing such a container with a beverage.
  • the content of Cyclo(Leu-Glu) or a salt thereof contained in the composition of the present invention is not particularly limited, and can be set according to its form and the like.
  • the content of Cyclo(Leu-Glu) or a salt thereof in the composition of the present invention may be, for example, 0.000001% by weight or more, preferably 0.00001% by weight or more, and 0.0001% by weight. % or more is more preferable, 0.001% by weight or more is still more preferable, 0.01% by weight or more is particularly preferable, and 50% by weight or less is preferable.
  • the content of Cyclo(Leu-Glu) or a salt thereof may be, for example, 0.000001 to 25% by weight, preferably 0.00001 to 10% by weight, in the composition of the present invention. 0.0001 to 5% by weight is more preferred, 0.001 to 5% by weight is even more preferred, and 0.01 to 1% by weight is particularly preferred.
  • Cyclo(Leu-Glu) and salts thereof can be quantified by a known method, for example, by liquid chromatography mass spectrometry (LC/MS).
  • the composition of the present invention is preferably taken orally (orally administered).
  • the dose (which can also be referred to as intake) of the composition of the present invention may be an amount that suppresses or improves cognitive function, and may be appropriately set according to the dosage form, administration method, body weight of the subject, and the like.
  • the dosage of the composition of the present invention is preferably such that a ⁇ -secretase inhibitory effect is obtained.
  • the dose of the composition of the present invention is preferably an amount that provides an effect of suppressing the production and/or accumulation of amyloid ⁇ .
  • the dosage when the composition of the present invention is ingested or administered to a human (adult) subject, the dosage is preferably 0.001 mg or more per day as a dosage of Cyclo (Leu-Glu) , more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and preferably 5000 mg or less, more preferably 1000 mg or less, still more preferably 100 mg or less.
  • the dosage of Cyclo(Leu-Glu) or a salt thereof is, as Cyclo(Leu-Glu) per day, preferably 0.001 to 5000 mg, more preferably 0.01 to 1000 mg, still more preferably 0.1 to 100 mg.
  • Cyclo(Leu-Glu) or a salt thereof in the above amount is preferably taken or administered orally.
  • the composition of the present invention may be an oral composition for ingesting or administering Cyclo(Leu-Glu) or a salt thereof in the above amount per 60 kg body weight per day to humans.
  • composition of the present invention is preferably taken or administered continuously. Continuous ingestion or administration of Cyclo(Leu-Glu) or a salt thereof is expected to yield higher effects. In one aspect, the composition of the present invention is preferably taken or administered continuously for one week or longer, more preferably for four weeks or longer, and even more preferably for eight weeks or longer. Cyclo(Leu-Glu) or a salt thereof can be ingested as a food or drink, and from the viewpoint of safety, long-term ingestion is considered to have few problems.
  • Subjects to whom the composition of the present invention is ingested or administered are not particularly limited. Humans or non-human mammals are preferred, and humans are more preferred.
  • subjects to which the composition of the present invention is administered include subjects who need or want to suppress or improve cognitive function, subjects who need or want to suppress the production and/or accumulation of amyloid ⁇ , and amyloid.
  • administration subjects include subjects who need or desire prevention or improvement of memory function deterioration, subjects with memory function deterioration, and the like.
  • a decline in cognitive function may be a decline in cognitive function due to accumulation of amyloid ⁇ , a decline in cognitive function associated with aging, or the like.
  • administration subjects in the present invention include middle-aged and elderly people.
  • Middle-aged and elderly people include elderly people.
  • a middle-aged person may be, for example, a person over the age of 40.
  • elderly people are preferred as subjects.
  • a senior citizen may be, for example, a human over the age of 60 or over the age of 65.
  • the subject of administration of the composition of the present invention may be a healthy subject.
  • composition of the present invention has a label indicating that it has an effect of suppressing or improving cognitive function, or a function exhibited by suppressing or improving cognitive function, or suppressing the production and / or accumulation of amyloid ⁇ .
  • Such indication is also called functionality indication.
  • the display is not particularly limited. Such indications include, for example, "increases cognitive function”, “suppresses deterioration of cognitive function”, “maintains good cognitive function”, “improves memory”, “suppresses deterioration of memory”, and "improves memory”.
  • the composition of the present invention is preferably a food or drink labeled with one or more of the above labels.
  • the above indication may be an indication that the above composition is used to obtain the above functions.
  • the label may be attached to the composition itself, or may be attached to the container or packaging of the composition.
  • Cyclo(Leu-Glu) or a salt thereof is also useful as an active ingredient for suppressing the production and/or accumulation of amyloid ⁇ .
  • a composition for suppressing the production and/or accumulation of amyloid ⁇ , which contains Cyclo(Leu-Glu) or a salt thereof as an active ingredient, is also included in the present invention.
  • the composition for suppressing the production or accumulation of amyloid ⁇ can also be said to be an agent for suppressing the production and/or accumulation of amyloid ⁇ .
  • Cyclo(Leu-Glu) or salts thereof are useful, for example, for the prevention or amelioration of conditions or diseases associated with or caused by amyloid- ⁇ accumulation in the brain. Such conditions or diseases include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
  • Cyclo(Leu-Glu) or a salt thereof is also useful as an active ingredient for ⁇ -secretase inhibition.
  • Compositions for inhibiting ⁇ -secretase comprising Cyclo(Leu-Glu) or salts thereof are also included in the present invention.
  • a ⁇ -secretase inhibitory composition can also be referred to as a ⁇ -secretase inhibitor.
  • Preferred embodiments, preferred doses, subjects of administration, etc. of the composition for suppressing the production and/or accumulation of amyloid ⁇ and the composition for inhibiting ⁇ -secretase are the same as those for the above composition for suppressing or improving cognitive function.
  • the invention also includes the following methods and uses.
  • a method for suppressing deterioration of cognitive function or improving cognitive function comprising administering Cyclo(Leu-Glu) or a salt thereof.
  • a method for suppressing production and/or accumulation of amyloid ⁇ comprising administering Cyclo(Leu-Glu) or a salt thereof.
  • a method of inhibiting ⁇ -secretase comprising administering Cyclo(Leu-Glu) or a salt thereof.
  • the method may be a therapeutic method or a non-therapeutic method.
  • the use may be therapeutic or non-therapeutic.
  • Cyclo(Leu-Glu) or a salt thereof By administering Cyclo(Leu-Glu) or a salt thereof, it is possible to suppress or improve cognitive function decline. As a result, for example, memory loss, forgetfulness, aphasia, apraxia, agnosia, executive dysfunction, loss of concentration, loss of attention, loss of judgment, loss of spatial recognition, loss of cognitive flexibility, loss of executive function, and information processing. It is possible to prevent or improve speed reduction.
  • Cyclo(Leu-Glu) or a salt thereof is preferably used for suppressing or improving memory function (memory).
  • Cyclo(Leu-Glu) or a salt thereof can be used to suppress the production and/or accumulation of amyloid ⁇ through ⁇ -secretase inhibition.
  • ⁇ -secretase inhibition can suppress the production and/or accumulation of amyloid ⁇ , thereby suppressing cognitive decline or improving cognitive function.
  • Cyclo(Leu-Glu) or a salt thereof is used to suppress or improve cognitive decline associated with amyloid ⁇ accumulation.
  • Cyclo(Leu-Glu) or a salt thereof may be ingested or administered to the subject once or more times a day, for example, once to several times (for example, 2 to 3 times) a day. preferable.
  • the above uses are preferably in humans or non-human mammals, more preferably in humans.
  • Cyclo(Leu-Glu) or a salt thereof can be used to prevent or ameliorate a condition or disease associated with amyloid- ⁇ accumulation through ⁇ -secretase inhibition.
  • the present invention also includes a method for preventing or ameliorating a condition or disease associated with amyloid ⁇ accumulation, comprising administering Cyclo(Leu-Glu) or a salt thereof.
  • Cyclo(Leu-Glu) or a salt thereof may be used in an amount (which can also be called an effective amount) that suppresses or improves cognitive function.
  • the above-mentioned effective amount is preferably an amount such that an effect of suppressing the production and/or accumulation of amyloid ⁇ is obtained. Moreover, the above-mentioned effective amount is more preferably an amount that provides a ⁇ -secretase inhibitory effect.
  • Cyclo(Leu-Glu) or its salt is the same as the composition of the present invention described above with respect to the preferred dose, administration method, administration subject, and the like. Cyclo(Leu-Glu) or a salt thereof may be ingested or administered as is, or may be ingested or administered as a composition containing it. For example, a composition of the invention may be ingested or administered.
  • Cyclo(Leu-Glu) or a salt thereof can be used for the production of foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. used for suppressing deterioration of cognitive function or improving cognitive function.
  • Cyclo (Leu-Glu) or a salt thereof can be used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. used to suppress the production and/or accumulation of amyloid ⁇ . can.
  • the present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing or improving cognitive function decline.
  • the present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing the production and/or accumulation of amyloid ⁇ .
  • the present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the manufacture of a composition for inhibiting ⁇ -secretase. Cyclo(Leu-Glu) or a salt thereof can be used for the manufacture of a composition for preventing or improving conditions or diseases associated with amyloid ⁇ accumulation.
  • a range represented by “1-2” means from 1 to 2 and includes 1 and 2.
  • the upper limit and the lower limit may be any combination of ranges.
  • Examples 1 and 2 and Comparative Example 1> Evaluation of compounds having ⁇ -secretase inhibitory activity
  • Materials and Methods Test compounds were tested for ⁇ -secretase inhibitory activity.
  • test compounds cycloleucylalanine (Cyclo(Leu-Ala)) (Comparative Example 1) and cycloleucylglutamate (Cyclo(Leu-Glu)) (Examples 1 and 2) were used.
  • Cyclo (Leu-Ala) was purchased from Bachem
  • Cyclo (Leu-Glu) was purchased from Peptide Institute.
  • Beta Secretase (BACE1) Activity Assay Kit (abcam) was used to evaluate the ⁇ -secretase inhibitory activity.
  • the inhibitory effect on ⁇ -secretase enzymatic activity was evaluated according to the method described in the kit. After mixing the sample solution (test compound solution) and the enzyme solution on a 96 Well Plate (Corning), the mixture was preincubated at 37°C for 10 minutes. After that, a substrate solution was added and reacted at 37° C. for 60 minutes.
  • the concentration (final concentration) of each test compound in the evaluation was carried out as shown in Table 1.
  • the ⁇ fluorescence intensity of the reaction solution (fluorescence intensity at the end of the reaction (60 minutes) ⁇ fluorescence intensity before the start of the reaction (0 minutes)) was used to evaluate the enzyme activity.
  • a group to which no test compound was added was used as a control.
  • the inhibitory activity of each test compound was evaluated with the enzyme activity ( ⁇ fluorescence intensity) of Control as 1.
  • the BACE activity shown in FIG. 1 is a relative value of the BACE activity of the test compound ( ⁇ fluorescence intensity of the reaction solution to which the test compound was added) when the BACE activity of Control ( ⁇ fluorescence intensity of Control) is 1. No inhibitory activity was confirmed in cycloleucylalanine (Cyclo(Leu-Ala)) measured as Comparative Example 1, but cycloleucylglutamate (Cyclo(Leu-Glu)) (Examples 1 and 2) - A decrease in secretase enzymatic activity was observed.

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Abstract

The purpose of the present invention is to provide a composition for suppressing or ameliorating cognitive function decline. The present invention pertains to a composition for suppressing or ameliorating cognitive function decline, the composition containing cyclo(Leu-Glu) or a salt thereof as an active ingredient.

Description

認知機能の低下抑制又は改善用組成物Composition for suppressing or improving cognitive function decline
本発明は、認知機能の低下抑制又は改善用組成物などに関する。 TECHNICAL FIELD The present invention relates to a composition for suppressing or improving cognitive function, and the like.
記憶機能等の認知機能の改善は、世代に関係なく求められるものである。また近年、日本のように人口構成における高齢者比率が高い国では、加齢に伴う認知機能の低下が問題となっており、飲食品等として日常的に摂取することで認知機能の低下を抑制又は認知機能を改善することができる成分の探索が行われている。 Improvement of cognitive functions such as memory function is required regardless of generation. In recent years, in countries with a high percentage of elderly people in the population structure, such as Japan, the deterioration of cognitive function due to aging has become a problem. Or, a search is being made for ingredients that can improve cognitive function.
例えば、特許文献１では、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）を含有する認知機能の低下抑制及び／又は改善剤が開示されている。この認知機能の低下抑制及び／又は改善剤をヒトが経口摂取することによって、注意力・集中力、言語能力、視空間・構成能力が低下抑制及び／又は改善されることが開示されている。 For example, Patent Document 1 discloses an agent for suppressing and/or improving cognitive function deterioration containing Cyclo (Gly-Pro). It is disclosed that reduction in attention/concentration, language ability, visuospatial/constructive ability is suppressed and/or improved by oral ingestion of this agent for suppressing and/or improving cognitive function decline.
特開２０２０－１９６６８６号公報JP 2020-196686 A
上記の通り、従来、認知機能の低下抑制又は認知機能改善のための成分が探索され、特許文献１にも開示されているが、認知機能の低下を抑制又は認知機能を改善することができる更なる成分が求められている。 As described above, conventionally, a component for suppressing the decline of cognitive function or improving cognitive function has been searched for, and disclosed in Patent Document 1, but it is possible to suppress the decline of cognitive function or improve cognitive function. different ingredients are required.
本発明は、上記現状に鑑みてなされたものであり、認知機能の低下抑制又は改善用組成物を提供することを目的とする。 The present invention has been made in view of the above-mentioned current situation, and an object of the present invention is to provide a composition for suppressing or improving cognitive function decline.
本発明者らは、上記課題に鑑み鋭意研究した結果、環状ジペプチドであるシクロロイシルグルタメート（Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ））が、認知機能の低下抑制又は改善に有効であることを見出した。 As a result of intensive research in view of the above problems, the present inventors found that a cyclic dipeptide, cycloleucylglutamate (Cyclo(Leu-Glu)), is effective in suppressing or improving cognitive function.
すなわち、本発明は、これに限定されるものではないが、以下の認知機能の低下抑制又は改善用組成物等に関する。
〔１〕Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を有効成分として含む、認知機能の低下抑制又は改善用組成物。
〔２〕アミロイドβの産生及び／又は蓄積を抑制する、上記〔１〕に記載の組成物。
〔３〕β－セクレターゼを阻害することによりアミロイドβの産生及び／又は蓄積を抑制する、上記〔１〕又は〔２〕に記載の組成物。
〔４〕上記組成物が、経口用である、上記〔１〕～〔３〕のいずれかに記載の組成物。
〔５〕上記組成物が、飲食品又は医薬品である、上記〔１〕～〔４〕のいずれかに記載の組成物。
〔６〕上記組成物が、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」及び「論理的思考力を維持・改善する」からなる群より選択される１又は２以上の機能の表示を付されたものである、上記〔１〕～〔５〕のいずれかに記載の組成物。
〔７〕認知機能の低下抑制又は改善用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。
〔８〕認知機能の低下抑制又は改善のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。 That is, the present invention relates to, but is not limited to, the following composition for suppressing or improving cognitive function.
[1] A composition for suppressing or improving cognitive function, comprising Cyclo(Leu-Glu) or a salt thereof as an active ingredient.
[2] The composition of [1] above, which suppresses the production and/or accumulation of amyloid β.
[3] The composition of [1] or [2] above, which suppresses the production and/or accumulation of amyloid β by inhibiting β-secretase.
[4] The composition according to any one of [1] to [3] above, which is for oral use.
[5] The composition according to any one of [1] to [4] above, which is a food or drink or a pharmaceutical.
[6] The composition "enhances cognitive function", "suppresses deterioration of cognitive function", "maintains good cognitive function", "improves memory", "suppresses deterioration of memory", "improves memory "maintaining good memory", "improving memory accuracy", "preventing memory impairment", "improving memory impairment", "maintaining memory as a part of cognitive function", and "preventing memory loss" functions that are suitable for people to become,""improve memory accuracy and judgment accuracy, which are part of cognitive function", "improve memory retention or consolidation", "maintain enhanced cognitive function", "improves executive function", "promotes attention and concentration", "improves learning ability", "maintains and improves orientation", "delays age-related cognitive decline", " labeled with one or more functions selected from the group consisting of "strengthening short-term and long-term memory", "promoting verbal and visuospatial memory" and "maintaining/improving logical thinking ability" The composition according to any one of [1] to [5] above.
[7] Use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing or improving cognitive function decline.
[8] Use of Cyclo (Leu-Glu) or a salt thereof for suppressing or improving cognitive function decline.
本発明によれば、認知機能の低下抑制又は改善用組成物を提供することができる。本発明の組成物は、認知機能の低下抑制又は改善のための飲食品、医薬品等として使用することができる。 INDUSTRIAL APPLICABILITY According to the present invention, a composition for suppressing or improving cognitive function can be provided. The composition of the present invention can be used as food, beverages, pharmaceuticals, etc. for suppressing or improving cognitive function.
図１は、被験化合物非添加群（Ｃｏｎｔｒｏｌ）、Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ）（比較例１）及び（Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）（実施例１、２）のβ－セクレターゼ（ＢＡＣＥ）阻害活性を示すグラフである。FIG. 1 shows the β-secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo (Leu-Ala) (Comparative Example 1) and (Cyclo (Leu-Glu) (Examples 1 and 2). graph.
本発明の認知機能の低下抑制又は改善用組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を含む。本発明の認知機能の低下抑制又は改善用組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を有効成分として含む。本明細書中、本発明の認知機能の低下抑制又は改善用組成物を、本発明の組成物ということもある。本発明の組成物は、認知機能の低下を抑制又は認知機能を改善するために使用されるものである。 The composition for suppressing or improving cognitive function decline of the present invention contains Cyclo(Leu-Glu) or a salt thereof. The composition for suppressing or improving cognitive function decline of the present invention contains Cyclo (Leu-Glu) or a salt thereof as an active ingredient. In the present specification, the composition for suppressing or improving cognitive function deterioration of the present invention may be referred to as the composition of the present invention. The composition of the present invention is used for suppressing deterioration of cognitive function or improving cognitive function.
本発明において使用されるＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）（シクロロイシルグルタメート）は、ロイシン及びグルタミン酸が縮合結合した構造を有する環状ジペプチドである。
本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、Ｎ末端側アミノ酸のアミノ基とＣ末端側アミノ酸のカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する化合物をいう。なお、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わなく、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）とＣｙｃｌｏ（Ｇｌｕ－Ｌｅｕ）（シクログルタミルロイシン／シクログルタメートロイシン）とは同じ環状ジペプチドを表す。 Cyclo(Leu-Glu) (cycloleucylglutamate) used in the present invention is a cyclic dipeptide having a structure in which leucine and glutamic acid are condensed.
As used herein, the term "cyclic dipeptide" is characterized by having amino acids as constituent units, and is a diketopiperazine structure produced by dehydration condensation between the amino group of the N-terminal side amino acid and the carboxyl group of the C-terminal side amino acid. A compound having In this specification, as long as the amino acid constitution of the cyclic dipeptides is the same, it does not matter which order they are described, Cyclo (Leu-Glu) and Cyclo (Glu-Leu) (cycloglutamyl leucine / cycloglutamate Leucine) represents the same cyclic dipeptide.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）の塩としては、薬理学的に許容される塩又は飲食品に許容される塩であれば特に限定されず、酸性塩及び塩基性塩のいずれであってもよい。酸性塩として、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩；酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩等の有機酸塩等が挙げられる。塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。 The salt of Cyclo(Leu-Glu) is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for food and drink, and may be either an acid salt or a basic salt. Acid salts include, for example, inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates; Examples include organic acid salts such as acid salts and propionate salts. Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）及びその塩の由来及び製造方法は特に制限されない。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、公知の方法に従って製造することができる。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）及びその塩は、天然物由来のものであってもよく、人工的に合成したものであってもよく、酵素法又は微生物発酵法により製造されてもよく、直鎖状ジペプチドを脱水及び環化させることによって合成されてもよい。例えば、コラーゲン加水分解物などのタンパク質加水分解物を加熱して、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）等の環状ジペプチドを豊富に含むペプチド熱処理物を得ることができる。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、これを含むタンパク質加水分解物又はその熱処理物を使用して組成物に配合してもよいし、タンパク質加水分解物若しくはその熱処理物の濃縮物、乾燥粉末又は精製度を高めたものを使用して組成物に配合してもよい。本発明の組成物は、例えば、タンパク質加水分解物又はその熱処理物を含有し、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、タンパク質加水分解物又はその熱処理物の一部であってもよい。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）及びその塩は、市販品を使用することもできる。 The origin and production method of Cyclo(Leu-Glu) and salts thereof are not particularly limited. Cyclo(Leu-Glu) or a salt thereof can be produced according to a known method. Cyclo(Leu-Glu) and its salts may be derived from natural products, may be artificially synthesized, may be produced by an enzymatic method or a microbial fermentation method, may be linear It may be synthesized by dehydrating and cyclizing the dipeptide. For example, protein hydrolysates, such as collagen hydrolysates, can be heated to yield heat-treated peptides rich in cyclic dipeptides, such as Cyclo (Leu-Glu).
Cyclo(Leu-Glu) or a salt thereof may be incorporated into the composition using a protein hydrolyzate containing it or a heat-treated product thereof, or a concentrate, dry powder of the protein hydrolyzate or heat-treated product thereof. Or you may mix|blend in a composition using what raised the refinement|purification. The composition of the present invention contains, for example, a protein hydrolyzate or heat-treated product thereof, and Cyclo(Leu-Glu) or a salt thereof may be part of the protein hydrolyzate or heat-treated product thereof. Cyclo (Leu-Glu) and salts thereof can also be used as commercially available products.
後述の実施例で示されるように、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）は、β－セクレターゼ阻害作用を有する。β－セクレターゼは、アミロイドβ（Ａβ）の産生に関与する酵素である。
アミロイドβは、アミロイドβタンパク質、アミロイドβペプチド又はβアミロイドと呼ばれることもあるペプチドである。アミロイドβは、通常、４０個前後のアミノ酸からなるペプチドであり、アミロイドβ１－４２、アミロイドβ１－４０等が挙げられる。非会合状態のアミロイドβは、アミロイドβモノマーと呼ばれることもある。アミロイドβが凝集してオリゴマー化又は線維化すると、神経細胞毒性を示す。また、凝集したアミロイドβは脳から排出されずに蓄積し、アルツハイマー病（アルツハイマー型認知症）発症の引き金になると考えられている。従って、アミロイドβの産生及び／又は蓄積を抑制することは、アルツハイマー病の予防又は病気の進行の抑制に有効であり、認知機能の低下抑制又は改善に有効である。 Cyclo(Leu-Glu) has a β-secretase inhibitory effect, as shown in the examples below. β-secretase is the enzyme involved in the production of amyloid β (Aβ).
Amyloid-β is a peptide sometimes referred to as amyloid-β protein, amyloid-β peptide or β-amyloid. Amyloid β is usually a peptide consisting of around 40 amino acids, and includes amyloid β 1-42 , amyloid β 1-40 and the like. Unassociated amyloid-β is sometimes referred to as amyloid-β monomer. When amyloid β aggregates to oligomerize or fibrillate, it exhibits neuronal toxicity. In addition, aggregated amyloid β accumulates without being discharged from the brain, and is considered to trigger the onset of Alzheimer's disease (Alzheimer's dementia). Therefore, suppression of the production and/or accumulation of amyloid β is effective in preventing Alzheimer's disease or in suppressing progression of the disease, and in suppressing or improving cognitive function.
アミロイドβは、アミロイドβ前駆体タンパク質（ＡＰＰ）が、β－セクレターゼ及びγ－セクレターゼによって２段階で切断されて生成する。β－セクレターゼは、アミロイドβ産生の律速酵素であり、その切断が総アミロイドβ産生量を規定している。このため、β－セクレターゼを阻害することによって、アミロイドβの産生を抑制することができ、アミロイドβの蓄積を抑制することができる。 Amyloid β is produced by the two-step cleavage of amyloid β precursor protein (APP) by β-secretase and γ-secretase. β-Secretase is the rate-limiting enzyme for amyloid β production, and its cleavage regulates the total amyloid β production. Therefore, by inhibiting β-secretase, the production of amyloid β can be suppressed, and the accumulation of amyloid β can be suppressed.
本発明の組成物は、アミロイドβの産生及び／又は蓄積を抑制するために有用である。一態様にいて、本発明の組成物は、β－セクレターゼを阻害することにより、アミロイドβの産生を抑制するため、及び／又は、蓄積を抑制するために使用することができる。一態様において、本発明の組成物は、アミロイドβの産生及び／又は蓄積を抑制することによって、認知機能の低下を抑制又は認知機能を改善するために使用することができる。
本発明におけるアミロイドβには、非会合状態のアミロイドβ、オリゴマー等の凝集体を形成しているアミロイドβが含まれる。凝集体として、アミロイドβが２個以上（例えば２～５０個）凝集した可溶性凝集体（アミロイドβオリゴマー）が挙げられる。 The composition of the present invention is useful for suppressing the production and/or accumulation of amyloid β. In one aspect, the composition of the present invention can be used to suppress the production and/or accumulation of amyloid β by inhibiting β-secretase. In one aspect, the composition of the present invention can be used to suppress deterioration of cognitive function or improve cognitive function by suppressing the production and/or accumulation of amyloid β.
Amyloid β in the present invention includes non-aggregated amyloid β and amyloid β forming aggregates such as oligomers. Aggregates include soluble aggregates (amyloid β oligomers) in which 2 or more (eg, 2 to 50) amyloid β aggregates.
本発明において、上記認知機能は、記憶機能、照合機能、統合機能、遂行機能、注意力（注意機能）、集中力等の脳の機能を意味する。
本発明において、認知機能の低下抑制は、認知機能の維持、認知機能の低下の進行を遅延させること、認知機能の低下を停止させること等を含む。認知機能の改善は、認知機能障害の改善（例えば、認知機能障害の程度の軽減（緩和））、認知機能の回復、認知機能の向上等を含む。認知機能障害は、上記認知機能の一部又は全部が機能を果たさないことを意味する。認知機能の低下抑制又は改善は、一部の認知機能の低下抑制又は改善を含む。回復は、少なくとも部分的に回復させることを含む。 In the present invention, the cognitive function means brain functions such as memory function, matching function, integration function, executive function, attention (attentive function), and concentration.
In the present invention, suppression of decline in cognitive function includes maintenance of cognitive function, delay in progression of decline in cognitive function, and halting decline in cognitive function. Improvement of cognitive function includes improvement of cognitive impairment (eg, reduction (mitigation) of degree of cognitive impairment), recovery of cognitive function, enhancement of cognitive function, and the like. Cognitive impairment means failure of some or all of the above cognitive functions. Suppression or improvement of cognitive function decline includes suppression or improvement of some cognitive function decline. Recovering includes recovering at least partially.
認知機能の低下や認知機能障害の原因としては、加齢のほか、アルツハイマー病やピック病・びまん性レビー小体病等の神経変性疾患、脳梗塞や脳出血・慢性硬膜下血腫・脳腫瘍・脳炎・正常圧水頭症等の脳疾患、クロイツフェルト・ヤコブ病等が挙げられる。
一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を含む組成物は、アルツハイマー病による認知機能の低下抑制のため、アルツハイマー病による認知機能障害の改善のために好適に使用される。加齢に伴う認知機能障害は、中高年者における加齢に伴う認知機能障害であってよい。中高年者は、高齢者を含む。 The causes of cognitive decline and cognitive dysfunction include aging, neurodegenerative diseases such as Alzheimer's disease, Pick's disease, and diffuse Lewy body disease, cerebral infarction, cerebral hemorrhage, chronic subdural hematoma, brain tumor, and encephalitis.・Cerebral diseases such as normal pressure hydrocephalus, Creutzfeldt-Jakob disease, etc.
In one aspect, a composition containing Cyclo(Leu-Glu) or a salt thereof is suitably used for suppressing deterioration of cognitive function due to Alzheimer's disease and improving cognitive impairment due to Alzheimer's disease. The age-related cognitive impairment may be age-related cognitive impairment in middle-aged and elderly individuals. Middle-aged and elderly people include elderly people.
一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を含む組成物は、記憶機能、遂行機能、注意力及び集中力からなる群より選択される少なくとも１つの認知機能の低下抑制又は改善のために好適に使用される。本発明の組成物は、例えば、アルツハイマー病による記憶機能、遂行機能、注意力及び集中力からなる群より選択される少なくとも１つの認知機能の低下抑制又はアルツハイマー病により低下した上記の認知機能を改善するために使用することができる。 In one aspect, the composition containing Cyclo (Leu-Glu) or a salt thereof is used for suppressing or improving at least one cognitive function selected from the group consisting of memory function, executive function, attention and concentration. preferably used. The composition of the present invention, for example, suppresses the deterioration of at least one cognitive function selected from the group consisting of memory function, executive function, attention and concentration due to Alzheimer's disease, or improves the above cognitive function that has been deteriorated due to Alzheimer's disease. can be used to
記憶機能とは、過去経験を保持し、後にそれを再現して利用する機能のことである。上記記憶機能は、例えば言語的記憶機能、非言語的記憶機能、視空間記憶機能、要点記憶機能及び作業記憶機能等に分類される。 The memory function is the ability to retain past experiences and use them later by reproducing them. The memory functions are classified into, for example, verbal memory functions, non-verbal memory functions, visuospatial memory functions, gist memory functions, working memory functions, and the like.
遂行機能とは、目標を達成するために計画的に段取りをつけて行動する機能で、人間が社会的、自立的、創造的な活動を行うために非常な重要な機能である。遂行機能は、視覚、聴覚、嗅覚等の様々な情報と過去の経験をすり合わせて、前頭葉で調整される。 The executive function is the ability to act systematically in order to achieve a goal, and is a very important function for humans to carry out social, independent, and creative activities. Executive functions are coordinated in the frontal lobe by combining various information such as visual, auditory, and olfactory information with past experiences.
注意力とは、多くの情報の中から情報を選択する機能であり、脳の限られた処理資源を有効に活用するために、不要な情報には処理資源を割り当てず、必要な情報だけを優先的に処理するという情報の選択的処理機能である。
集中力とは、雑念を払いながら、精神的な力を投入し、目の前の課題に対して効果的に注意を集中させる機能である。
一態様において、本発明の組成物は、記憶機能の低下抑制又は改善のために好適に使用され、言語的記憶機能、非言語的記憶機能、視空間記憶機能、要点記憶機能及び作業記憶機能の低下抑制又は改善のためにより好適に使用される。 Attention is the ability to select information from among a large amount of information.In order to effectively utilize the limited processing resources of the brain, we do not allocate processing resources to unnecessary information and only focus on necessary information. It is a selective processing function of information that is preferentially processed.
Concentration is the ability to effectively concentrate attention on the task at hand by throwing in mental power while clearing away distractions.
In one aspect, the composition of the present invention is preferably used for suppressing or improving memory function deterioration, and is useful for improving verbal memory function, non-verbal memory function, visuospatial memory function, gist memory function and working memory function. It is more preferably used for suppression of deterioration or improvement.
一態様において、本発明の組成物は、例えば、認知機能の低下を呈する状態又は疾患、脳におけるアミロイドβの蓄積に関連する状態又は疾患の予防又は改善のために使用することができる。このような状態又は疾患として、例えば、アルツハイマー病（アルツハイマー型認知症を含む）、軽度認知障害等が挙げられる。
本発明の組成物は、上記の状態又は疾患を予防又は改善するために使用することができ、上記の状態又は疾患の予防に好適に使用することができる。
本明細書において、状態又は疾患の予防は、発症を防止すること、発症を遅延させること、発症率を低下させること、発症のリスクを軽減すること等を包含する。状態又は疾患の改善は、対象を状態又は疾患から回復させること、状態又は疾患の症状を軽減すること、状態又は疾患の症状を好転させること、状態又は疾患の進行を遅延させること、防止すること等を包含する。 In one aspect, the composition of the present invention can be used, for example, for the prevention or amelioration of conditions or diseases exhibiting cognitive decline, conditions or diseases associated with accumulation of amyloid β in the brain. Such conditions or diseases include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
The composition of the present invention can be used to prevent or ameliorate the above conditions or diseases, and can be preferably used for the prevention of the above conditions or diseases.
As used herein, prevention of a condition or disease includes preventing onset, delaying onset, reducing the rate of onset, reducing risk of onset, and the like. Ameliorating a condition or disease includes ameliorating the subject from the condition or disease, alleviating symptoms of the condition or disease, ameliorating symptoms of the condition or disease, slowing progression of the condition or disease, preventing the condition or disease. etc.
アルツハイマー病及び軽度認知障害では、認知機能が低下することが知られている。アルツハイマー病、軽度認知障害における認知機能低下の症状として、例えば、記憶力低下、記憶障害（物忘れ）、失語（ものの名前が出にくくなる）、失行、失認（よく知っているはずの場所で道に迷う等）、見当識（場所、時間、人の名前など、自分が置かれた状況を正しく認識する能力）の低下、言語及び非言語学習能力の低下、聴覚及び視覚処理の低下、遂行機能低下、遂行機能障害（計画を立てて物事を行うことができなくなる）、集中力低下、注意力低下、判断力低下、空間認識力低下、認知柔軟性低下、情報処理速度低下等が挙げられる。本発明の組成物は、例えば、上記の症状の予防又は改善のために使用することができる。 Cognitive function is known to decline in Alzheimer's disease and mild cognitive impairment. Symptoms of cognitive decline in Alzheimer's disease and mild cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficult to name things), apraxia, agnosia (walking in familiar places). (e.g., getting lost), decreased orientation (the ability to correctly recognize one's own situation, such as place, time, name of person, etc.), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, executive function executive dysfunction (inability to plan and do things), decreased ability to concentrate, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, decreased information processing speed, etc. The composition of the present invention can be used, for example, for prevention or amelioration of the above symptoms.
本発明の組成物は、治療的用途（医療用途）又は非治療的用途（非医療用途）のいずれにも適用することができる。非治療的とは、医療行為、すなわち人間の手術、治療又は診断を含まない概念である。
本発明の認知機能の低下抑制又は改善用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、又は、当該剤を含む組成物として提供することもできる。
一態様において、本発明の認知機能の低下抑制又は改善用組成物は、認知機能の低下抑制又は改善剤ということもできる。 The compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use). Non-therapeutic is a concept that does not involve medical intervention, i.e. human surgery, treatment or diagnosis.
The composition for suppressing or improving cognitive function decline of the present invention can be provided in the form of an agent as an example, but is not limited to this form. The agent itself can be provided as a composition, or a composition containing the agent can be provided.
In one aspect, the composition for suppressing or improving cognitive function decline of the present invention can also be said to be an agent for suppressing or improving cognitive function decline.
本発明の組成物は、経口用又は非経口用のいずれであってもよい。本発明の組成物は、好ましくは経口用組成物である。本発明の組成物は、例えば、飲食品、医薬品、医薬部外品、飼料等の形態とすることができ、飲食品又は医薬品が好ましい。本発明の組成物は、飲食品、医薬品、医薬部外品、飼料等に添加して使用することもできる。本発明の組成物の形態は特に限定されず、固体状（例えば、粉末状、顆粒状、タブレット状等）、液状、ペースト状等のいずれであってもよい。 The compositions of the invention may be either oral or parenteral. The compositions of the invention are preferably oral compositions. The composition of the present invention can be in the form of, for example, foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. Foods, beverages, or pharmaceuticals are preferred. The composition of the present invention can also be used by adding it to foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like. The form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granule, tablet, etc.), liquid, paste, or the like.
本発明の組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を含み、更に飲食品又は医薬品等への添加物として許容されている各種の希釈剤、酸味料、抗酸化剤、安定剤、保存料、香料、乳化剤、色素類、調味料、ｐＨ調整剤、栄養強化剤等が添加されていてもよい。 The composition of the present invention contains Cyclo (Leu-Glu) or a salt thereof, and further contains various diluents, acidulants, antioxidants, stabilizers, preservatives, etc. that are acceptable as additives for foods, beverages, pharmaceuticals, etc. Ingredients, flavors, emulsifiers, pigments, seasonings, pH adjusters, nutritional enhancers, and the like may be added.
例えば、本発明の組成物を飲食品とする場合、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩に、飲食品に使用可能な成分（例えば、食品素材、必要に応じて使用される食品添加物等）を配合して、種々の飲食品とすることができる。飲食品は特に限定されず、例えば、一般的な飲食品、健康食品、機能性表示食品、特定保健用食品、健康補助食品、病者用食品等が挙げられる。上記健康食品、機能性表示食品、特定保健用食品、健康補助食品等は、例えば、液剤、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、チュアブル剤、ドライシロップ剤、流動食等の各種製剤形態として使用することができる。 For example, when the composition of the present invention is used as a food or drink, Cyclo (Leu-Glu) or a salt thereof may be added to ingredients that can be used for food or drink (e.g., food materials, food additives used as necessary). can be blended to make various food and drink products. Food and drink are not particularly limited, and examples thereof include general food and drink, health food, food with function claims, food for specified health use, health supplement, and food for the sick. Health foods, foods with function claims, foods for specified health uses, health supplements, etc. are various formulations such as liquids, fine granules, tablets, granules, powders, capsules, chewable formulations, dry syrups, and liquid diets. Can be used as a form.
本発明の組成物を医薬品又は医薬部外品とする場合、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩に、薬理学的に許容される担体、必要に応じて添加される添加剤等を配合して、各種剤形の医薬品又は医薬部外品とすることができる。そのような担体、添加剤等は、医薬品又は医薬部外品に使用可能な、薬理学的に許容されるものであればよく、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤等の１又は２以上が挙げられる。医薬品又は医薬部外品の投与（摂取）形態としては、経口又は非経口（経皮、経粘膜、経腸、注射等）投与の形態が挙げられる。本発明の組成物を医薬品又は医薬部外品とする場合、経口用医薬品又は経口用医薬部外品とすることが好ましい。経口投与のための剤形としては、例えば、液剤、錠剤、散剤、細粒剤、顆粒剤、糖衣錠、カプセル剤、懸濁液、乳剤、チュアブル剤等が挙げられる。非経口投与のための剤形としては、例えば、注射剤、点滴剤、軟膏剤、ローション剤、貼付剤、坐剤、経鼻剤、経肺剤（吸入剤）等が挙げられる。医薬品は、非ヒト動物用医薬であってもよい。 When the composition of the present invention is used as a drug or quasi-drug, Cyclo (Leu-Glu) or a salt thereof is blended with a pharmacologically acceptable carrier, an optional additive, etc. , various dosage forms of pharmaceuticals or quasi-drugs. Such carriers, additives, etc. may be those that can be used for pharmaceuticals or quasi-drugs and are pharmacologically acceptable. One or more of antioxidants, coloring agents and the like can be mentioned. Examples of administration (ingestion) forms of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, enteral, injection, etc.) forms of administration. When the composition of the present invention is used as a drug or quasi-drug, it is preferably an oral drug or oral quasi-drug. Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, dragees, capsules, suspensions, emulsions, chewables and the like. Dosage forms for parenteral administration include, for example, injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants) and the like. The pharmaceutical may be a non-human veterinary pharmaceutical.
本発明の組成物を飼料とする場合には、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を飼料に配合すればよい。飼料には飼料添加剤も含まれる。飼料としては、例えば、牛、豚、鶏、羊、馬等に用いる家畜用飼料；ウサギ、ラット、マウス等に用いる小動物用飼料；犬、猫、小鳥等に用いるペットフードなどが挙げられる。 When the composition of the present invention is used as a feed, Cyclo (Leu-Glu) or a salt thereof may be added to the feed. Feed also includes feed additives. Examples of feeds include livestock feeds for cows, pigs, chickens, sheep, horses, etc.; small animal feeds for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.;
本発明の組成物を、例えば、飲食品、医薬品、医薬部外品、飼料等とする場合、その製造方法は特に限定されず、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を用いて、一般的な方法により製造することができる。 For example, when the composition of the present invention is used as a food or drink, a drug, a quasi-drug, a feed, etc., the production method is not particularly limited, and Cyclo (Leu-Glu) or a salt thereof may be used to prepare a general It can be manufactured by a method.
一態様において、本発明の組成物は、液状組成物であることが好ましく、飲料であることがより好ましい。飲料は、例えば、機能性飲料であってよい。飲料の形態は特に限定されず、容器詰飲料であってよい。容器詰飲料の容器は特に限定されず、いずれの形態及び材質の容器を用いてもよく、例えば、アルミ缶、スチール缶等の金属製容器；ペットボトル等の樹脂製容器；紙パック等の紙容器；ガラス瓶等のガラス製容器；樽等の木製容器等の通常用いられる容器のいずれも用いることができる。このような容器に飲料を充填及び密閉することにより、容器詰飲料が得られる。 In one aspect, the composition of the present invention is preferably a liquid composition, more preferably a beverage. The beverage may be, for example, a functional beverage. The form of the beverage is not particularly limited, and may be a packaged beverage. Containers for packaged beverages are not particularly limited, and containers of any shape and material may be used. For example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; Containers; glass containers such as glass bottles; and wooden containers such as barrels. Any of commonly used containers can be used. A packaged beverage is obtained by filling and sealing such a container with a beverage.
本発明の組成物に含まれるＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の含有量は特に限定されず、その形態等に応じて設定することができる。
一態様において、本発明の組成物におけるＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の含有量は、例えば、０．０００００１重量％以上であってよく、０．００００１重量％以上が好ましく、０．０００１重量％以上がより好ましく、０．００１重量％以上が更に好ましく、０．０１重量％以上が特に好ましく、また、５０重量％以下が好ましい。一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の含有量は、例えば、本発明の組成物中に０．０００００１～２５重量％であってよく、０．００００１～１０重量％が好ましく、０．０００１～５重量％がより好ましく、０．００１～５重量％が更に好ましく、０．０１～１重量％が特に好ましい。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）及びその塩は、例えば、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ）により公知の方法で定量することが可能である。 The content of Cyclo(Leu-Glu) or a salt thereof contained in the composition of the present invention is not particularly limited, and can be set according to its form and the like.
In one aspect, the content of Cyclo(Leu-Glu) or a salt thereof in the composition of the present invention may be, for example, 0.000001% by weight or more, preferably 0.00001% by weight or more, and 0.0001% by weight. % or more is more preferable, 0.001% by weight or more is still more preferable, 0.01% by weight or more is particularly preferable, and 50% by weight or less is preferable. In one aspect, the content of Cyclo(Leu-Glu) or a salt thereof may be, for example, 0.000001 to 25% by weight, preferably 0.00001 to 10% by weight, in the composition of the present invention. 0.0001 to 5% by weight is more preferred, 0.001 to 5% by weight is even more preferred, and 0.01 to 1% by weight is particularly preferred.
Cyclo(Leu-Glu) and salts thereof can be quantified by a known method, for example, by liquid chromatography mass spectrometry (LC/MS).
本発明の組成物は、経口で摂取（経口投与）されることが好ましい。本発明の組成物の投与量（摂取量ということもできる）は特に限定されない。本発明の組成物の投与量は、認知機能の低下抑制又は改善効果が得られるような量であればよく、投与形態、投与方法、対象の体重等に応じて適宜設定すればよい。本発明の組成物の投与量は、β－セクレターゼ阻害効果が得られるような量であることが好ましい。また、本発明の組成物の投与量は、アミロイドβの産生抑制及び／又は蓄積抑制効果が得られるような量が好ましい。 The composition of the present invention is preferably taken orally (orally administered). There is no particular limitation on the dose (which can also be referred to as intake) of the composition of the present invention. The dosage of the composition of the present invention may be an amount that suppresses or improves cognitive function, and may be appropriately set according to the dosage form, administration method, body weight of the subject, and the like. The dosage of the composition of the present invention is preferably such that a β-secretase inhibitory effect is obtained. In addition, the dose of the composition of the present invention is preferably an amount that provides an effect of suppressing the production and/or accumulation of amyloid β.
一態様において、本発明の組成物をヒト（成人）を対象に摂取させる又は投与する場合、その投与量は、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）の投与量として、１日あたり、好ましくは０．００１ｍｇ以上、より好ましくは０．０１ｍｇ以上、さらに好ましくは０．１ｍｇ以上、また、好ましくは５０００ｍｇ以下、より好ましくは１０００ｍｇ以下、さらに好ましくは１００ｍｇ以下である。一態様において、本発明の組成物をヒト（成人）に摂取させる又は投与する場合、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の投与量は、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）として、１日あたり、好ましくは０．００１～５０００ｍｇ、より好ましくは０．０１～１０００ｍｇ、さらに好ましくは０．１～１００ｍｇである。
上記量を、１日１回以上、例えば、１日１回で又は数回（例えば２～３回）に分けて、摂取又は投与することが好ましい。一態様においては、上記量のＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を、経口で摂取させる又は投与することが好ましい。ヒト（成人）の場合、１日当たり体重６０ｋｇ当たり上記量のＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を摂取させる又は投与することが好ましい。一態様において、本発明の組成物は、ヒトに、体重６０ｋｇあたり、１日あたり上記量のＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を摂取させる又は投与するための経口用組成物であってよい。 In one aspect, when the composition of the present invention is ingested or administered to a human (adult) subject, the dosage is preferably 0.001 mg or more per day as a dosage of Cyclo (Leu-Glu) , more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and preferably 5000 mg or less, more preferably 1000 mg or less, still more preferably 100 mg or less. In one aspect, when the composition of the present invention is ingested or administered to humans (adults), the dosage of Cyclo(Leu-Glu) or a salt thereof is, as Cyclo(Leu-Glu) per day, preferably 0.001 to 5000 mg, more preferably 0.01 to 1000 mg, still more preferably 0.1 to 100 mg.
It is preferable to take or administer the above amount once or more a day, for example, once a day or divided into several times (eg, 2 to 3 times). In one aspect, Cyclo(Leu-Glu) or a salt thereof in the above amount is preferably taken or administered orally. For humans (adults), it is preferable to ingest or administer Cyclo(Leu-Glu) or a salt thereof in the above amount per 60 kg body weight per day. In one aspect, the composition of the present invention may be an oral composition for ingesting or administering Cyclo(Leu-Glu) or a salt thereof in the above amount per 60 kg body weight per day to humans.
本発明の組成物は、継続して摂取又は投与されるものであることが好ましい。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を継続的に摂取させる又は投与することによって、より高い効果が得られることが期待される。一態様において、本発明の組成物は、好ましくは１週間以上、より好ましくは４週間以上、さらに好ましくは８週間以上継続して摂取又は投与されることが好ましい。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、飲食品などとして摂取可能であり、安全性の観点から、例えば長期摂取することにも問題が少ないと考えられる。 The composition of the present invention is preferably taken or administered continuously. Continuous ingestion or administration of Cyclo(Leu-Glu) or a salt thereof is expected to yield higher effects. In one aspect, the composition of the present invention is preferably taken or administered continuously for one week or longer, more preferably for four weeks or longer, and even more preferably for eight weeks or longer.
Cyclo(Leu-Glu) or a salt thereof can be ingested as a food or drink, and from the viewpoint of safety, long-term ingestion is considered to have few problems.
本発明の組成物を摂取させる又は投与する対象（投与対象ということもできる）は、特に限定されない。好ましくはヒト又は非ヒト哺乳動物であり、より好ましくはヒトである。
一態様において、本発明の組成物の投与対象として、認知機能の低下抑制又は改善を必要とする又は希望する対象、アミロイドβの産生抑制及び／又は蓄積抑制を必要とする又は希望する対象、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善を必要とする又は希望する対象等が挙げられる。一態様において、投与対象として、記憶機能低下の予防又は改善を必要とする又は希望する対象、記憶機能が低下した対象等が挙げられる。認知機能の低下は、アミロイドβの蓄積による認知機能の低下、加齢に伴う認知機能の低下等であってよい。一態様において、本発明における投与対象として、中高年者が挙げられる。中高年者は、高齢者を含む。中高年者は、例えば、４０歳以上のヒトであってよい。一態様において中高年者の中でも、対象として高齢者が好ましい。高齢者は、例えば、６０歳以上又は６５歳以上のヒトであってよい。一態様において、本発明の組成物の投与対象は、健常者であってよい。例えば、認知機能の低下抑制又は改善により予防又は改善が期待できる状態又は疾患の予防、脳内におけるアミロイドβの産生抑制及び／又は蓄積抑制、脳内におけるアミロイドβの蓄積予防、アルツハイマー病又は軽度認知障害の予防等を目的として、健常者に対して使用することもできる。 Subjects to whom the composition of the present invention is ingested or administered (can also be referred to as administration subjects) are not particularly limited. Humans or non-human mammals are preferred, and humans are more preferred.
In one aspect, subjects to which the composition of the present invention is administered include subjects who need or want to suppress or improve cognitive function, subjects who need or want to suppress the production and/or accumulation of amyloid β, and amyloid. Subjects who need or desire prevention or amelioration of conditions or diseases associated with β accumulation, and the like. In one aspect, administration subjects include subjects who need or desire prevention or improvement of memory function deterioration, subjects with memory function deterioration, and the like. A decline in cognitive function may be a decline in cognitive function due to accumulation of amyloid β, a decline in cognitive function associated with aging, or the like. In one aspect, administration subjects in the present invention include middle-aged and elderly people. Middle-aged and elderly people include elderly people. A middle-aged person may be, for example, a person over the age of 40. In one aspect, among middle-aged and elderly people, elderly people are preferred as subjects. A senior citizen may be, for example, a human over the age of 60 or over the age of 65. In one aspect, the subject of administration of the composition of the present invention may be a healthy subject. For example, prevention of conditions or diseases that can be expected to be prevented or improved by suppressing or improving cognitive function decline, suppression of amyloid β production and/or accumulation in the brain, prevention of amyloid β accumulation in the brain, Alzheimer's disease, or mild cognition It can also be used for healthy people for the purpose of preventing disorders.
本発明の組成物には、認知機能の低下抑制又は改善作用を有する旨の表示、又は、認知機能の低下抑制又は改善により発揮される機能、アミロイドβの産生抑制及び／又は蓄積抑制により発揮される機能の表示が付されていてもよい。このような表示は機能性表示ともいう。上記表示は、特に限定されない。このような表示として、例えば、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」、「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」、「論理的思考力を維持・改善する」、及び、これらと同視できる表示又は機能性表示が挙げられる。
本発明の一態様において、本発明の組成物は、上記の表示が１又は２以上付された飲食品であることが好ましい。また上記の表示は、上記の機能を得るために上記組成物を用いる旨の表示であってもよい。当該表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 The composition of the present invention has a label indicating that it has an effect of suppressing or improving cognitive function, or a function exhibited by suppressing or improving cognitive function, or suppressing the production and / or accumulation of amyloid β. may be labeled with functions that Such indication is also called functionality indication. The display is not particularly limited. Such indications include, for example, "increases cognitive function", "suppresses deterioration of cognitive function", "maintains good cognitive function", "improves memory", "suppresses deterioration of memory", and "improves memory". "maintaining good memory", "improving memory accuracy", "preventing memory impairment", "improving memory impairment", "maintaining memory as a part of cognitive function", and "preventing memory loss" functions that are suitable for people to become,""improve memory accuracy and judgment accuracy, which are part of cognitive function", "improve memory retention or consolidation", "maintain enhanced cognitive function", "improves executive function", "promotes attention and concentration", "improves learning ability", "maintains and improves orientation", "delays age-related cognitive decline", Examples include "strengthening short-term and long-term memory", "promoting verbal and visuospatial memory", "maintaining/improving logical thinking ability", and indications or functional indications equated with these.
In one aspect of the present invention, the composition of the present invention is preferably a food or drink labeled with one or more of the above labels. Moreover, the above indication may be an indication that the above composition is used to obtain the above functions. The label may be attached to the composition itself, or may be attached to the container or packaging of the composition.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、アミロイドβの産生及び／又は蓄積抑制のための有効成分としても有用である。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を有効成分として含む、アミロイドβの産生及び／又は蓄積抑制用組成物も、本発明に包含される。一態様において、アミロイドβの産生抑制又は蓄積抑制用組成物は、アミロイドβの産生抑制及び／又は蓄積抑制剤ということもできる。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、例えば、脳におけるアミロイドβの蓄積を伴う又はアミロイドβの蓄積に起因する状態又は疾患の予防又は改善のために有用である。このような状態又は疾患として、例えば、アルツハイマー病（アルツハイマー型認知症を含む）、軽度認知障害等が挙げられる。 Cyclo(Leu-Glu) or a salt thereof is also useful as an active ingredient for suppressing the production and/or accumulation of amyloid β. A composition for suppressing the production and/or accumulation of amyloid β, which contains Cyclo(Leu-Glu) or a salt thereof as an active ingredient, is also included in the present invention. In one aspect, the composition for suppressing the production or accumulation of amyloid β can also be said to be an agent for suppressing the production and/or accumulation of amyloid β. Cyclo(Leu-Glu) or salts thereof are useful, for example, for the prevention or amelioration of conditions or diseases associated with or caused by amyloid-β accumulation in the brain. Such conditions or diseases include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、β－セクレターゼ阻害のための有効成分としても有用である。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を含む、β－セクレターゼ阻害用組成物も本発明に包含される。β－セクレターゼ阻害用組成物は、β－セクレターゼ阻害剤ということもできる。
アミロイドβの産生及び／又は蓄積抑制用組成物、β－セクレターゼ阻害用組成物の好ましい態様、好ましい投与量、投与対象等は、上記の認知機能の低下抑制又は改善用組成物と同じである。 Cyclo(Leu-Glu) or a salt thereof is also useful as an active ingredient for β-secretase inhibition. Compositions for inhibiting β-secretase comprising Cyclo(Leu-Glu) or salts thereof are also included in the present invention. A β-secretase inhibitory composition can also be referred to as a β-secretase inhibitor.
Preferred embodiments, preferred doses, subjects of administration, etc. of the composition for suppressing the production and/or accumulation of amyloid β and the composition for inhibiting β-secretase are the same as those for the above composition for suppressing or improving cognitive function.
本発明は、以下の方法及び使用も包含する。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を投与する、認知機能の低下抑制又は認知機能の改善方法。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を投与する、アミロイドβの産生抑制及び／又は蓄積抑制方法。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を投与する、β－セクレターゼ阻害方法。
認知機能の低下を抑制又は認知機能を改善するための、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。
アミロイドβの産生抑制及び／又は蓄積抑制のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。
β－セクレターゼを阻害するための、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。
上記方法は、治療的な方法であってもよく、非治療的な方法であってもよい。上記使用は、治療的な使用であってもよく、非治療的な使用であってもよい。 The invention also includes the following methods and uses.
A method for suppressing deterioration of cognitive function or improving cognitive function, comprising administering Cyclo(Leu-Glu) or a salt thereof.
A method for suppressing production and/or accumulation of amyloid β, comprising administering Cyclo(Leu-Glu) or a salt thereof.
A method of inhibiting β-secretase, comprising administering Cyclo(Leu-Glu) or a salt thereof.
Use of Cyclo(Leu-Glu) or a salt thereof for suppressing cognitive decline or improving cognitive function.
Use of Cyclo(Leu-Glu) or a salt thereof for suppressing production and/or accumulation of amyloid β.
Use of Cyclo(Leu-Glu) or its salts to inhibit β-secretase.
The method may be a therapeutic method or a non-therapeutic method. The use may be therapeutic or non-therapeutic.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を投与することにより、認知機能の低下抑制又は改善が可能となる。これにより、例えば、記憶力低下、物忘れ、失語、失行、失認、遂行機能障害、集中力低下、注意力低下、判断力低下、空間認識力低下、認知柔軟性低下、遂行機能低下、情報処理速度低下などの予防又は改善が可能となる。一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、記憶機能（記憶）の低下抑制又は改善のために好適に使用される。 By administering Cyclo(Leu-Glu) or a salt thereof, it is possible to suppress or improve cognitive function decline. As a result, for example, memory loss, forgetfulness, aphasia, apraxia, agnosia, executive dysfunction, loss of concentration, loss of attention, loss of judgment, loss of spatial recognition, loss of cognitive flexibility, loss of executive function, and information processing. It is possible to prevent or improve speed reduction. In one aspect, Cyclo(Leu-Glu) or a salt thereof is preferably used for suppressing or improving memory function (memory).
一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、β－セクレターゼ阻害によって、アミロイドβの産生を抑制するため、及び／又は、蓄積を抑制するために使用することができる。例えば、β－セクレターゼ阻害によって、アミロイドβの産生を抑制及び／又は蓄積を抑制することができ、これにより、認知機能の低下を抑制又は認知機能を改善することができる。一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、アミロイドβの蓄積に伴う認知機能低下の抑制又は改善のために使用される。 In one aspect, Cyclo(Leu-Glu) or a salt thereof can be used to suppress the production and/or accumulation of amyloid β through β-secretase inhibition. For example, β-secretase inhibition can suppress the production and/or accumulation of amyloid β, thereby suppressing cognitive decline or improving cognitive function. In one aspect, Cyclo(Leu-Glu) or a salt thereof is used to suppress or improve cognitive decline associated with amyloid β accumulation.
上記方法及び使用においては、１日に１回以上、例えば、１日１回～数回（例えば２～３回）、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を対象に摂取させる又は投与することが好ましい。上記の使用は、好ましくはヒト又は非ヒト哺乳動物、より好ましくはヒトにおける使用である。
一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、β－セクレターゼ阻害によって、アミロイドβの蓄積に関連する状態又は疾患を予防又は改善するために使用することができる。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を投与する、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善方法も本発明に包含される。 In the above methods and uses, Cyclo(Leu-Glu) or a salt thereof may be ingested or administered to the subject once or more times a day, for example, once to several times (for example, 2 to 3 times) a day. preferable. The above uses are preferably in humans or non-human mammals, more preferably in humans.
In one aspect, Cyclo(Leu-Glu) or a salt thereof can be used to prevent or ameliorate a condition or disease associated with amyloid-β accumulation through β-secretase inhibition. The present invention also includes a method for preventing or ameliorating a condition or disease associated with amyloid β accumulation, comprising administering Cyclo(Leu-Glu) or a salt thereof.
上記方法及び使用においては、認知機能の低下抑制又は改善効果が得られる量（有効量ということもできる）のＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を使用すればよい。上記有効量は、アミロイドβの産生抑制及び／又は蓄積抑制効果が得られるような量であることが好ましい。また、上記有効量は、β－セクレターゼ阻害効果が得られるような量であることがより好ましい。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の好ましい投与量、投与方法、投与対象等は上述した本発明の組成物と同じである。Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、そのまま摂取又は投与してもよく、これを含む組成物として摂取又は投与してもよい。例えば、本発明の組成物を摂取又は投与してもよい。 In the method and use described above, Cyclo(Leu-Glu) or a salt thereof may be used in an amount (which can also be called an effective amount) that suppresses or improves cognitive function. The above-mentioned effective amount is preferably an amount such that an effect of suppressing the production and/or accumulation of amyloid β is obtained. Moreover, the above-mentioned effective amount is more preferably an amount that provides a β-secretase inhibitory effect. Cyclo(Leu-Glu) or its salt is the same as the composition of the present invention described above with respect to the preferred dose, administration method, administration subject, and the like. Cyclo(Leu-Glu) or a salt thereof may be ingested or administered as is, or may be ingested or administered as a composition containing it. For example, a composition of the invention may be ingested or administered.
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、認知機能の低下抑制又は認知機能の改善のために使用される飲食品、医薬品、医薬部外品、飼料等の製造のために使用することができる。また、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、アミロイドβの産生抑制及び／又は蓄積抑制のために使用される飲食品、医薬品、医薬部外品、飼料等の製造のために使用することができる。一態様において、本発明は、認知機能の低下抑制又は改善用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用も包含する。一態様において、本発明は、アミロイドβの産生抑制及び／又は蓄積抑制用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用も包含する。本発明は、β－セクレターゼ阻害用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用も包含する。
Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩は、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善用組成物の製造のために使用することができる。 Cyclo(Leu-Glu) or a salt thereof can be used for the production of foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. used for suppressing deterioration of cognitive function or improving cognitive function. In addition, Cyclo (Leu-Glu) or a salt thereof can be used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. used to suppress the production and/or accumulation of amyloid β. can. In one aspect, the present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing or improving cognitive function decline. In one aspect, the present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing the production and/or accumulation of amyloid β. The present invention also includes the use of Cyclo(Leu-Glu) or a salt thereof in the manufacture of a composition for inhibiting β-secretase.
Cyclo(Leu-Glu) or a salt thereof can be used for the manufacture of a composition for preventing or improving conditions or diseases associated with amyloid β accumulation.
本明細書において下限値と上限値によって表されている数値範囲、即ち「下限値～上限値」は、それら下限値及び上限値を含む。例えば、「１～２」により表される範囲は、１以上２以下を意味し、１及び２を含む。本明細書において、上限及び下限は、いずれの組み合わせによる範囲としてもよい。 Numerical ranges represented by lower and upper limits herein, ie, "lower and upper limits", include these lower and upper limits. For example, a range represented by "1-2" means from 1 to 2 and includes 1 and 2. In this specification, the upper limit and the lower limit may be any combination of ranges.
以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。 EXAMPLES The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited by these examples.
＜実施例１、２及び比較例１＞
（β－セクレターゼ阻害活性を有する化合物の評価）
材料と方法
被験化合物について、βセクレターゼ阻害活性を調べた。被験化合物には、シクロロイシルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ））（比較例１）及びシクロロイシルグルタメート（Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ））（実施例１～２）を用いた。Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ）はＢａｃｈｅｍ社から、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）は株式会社ペプチド研究所から購入した。
いずれもβ－セクレターゼ阻害活性の評価には、市販のキットＢｅｔａ　Ｓｅｃｒｅｔａｓｅ　（ＢＡＣＥ１）　Ａｃｔｉｖｉｔｙ　Ａｓｓａｙ　Ｋｉｔ（ａｂｃａｍ）を用いた。キットに記載の方法に従って、β－セクレターゼ酵素活性の阻害効果を評価した。
９６　Ｗｅｌｌ　Ｐｌａｔｅ（Ｃｏｒｎｉｎｇ）上でサンプル液（被験化合物溶液）と酵素液を混合した後、３７℃で１０分間プレインキュベートした。その後、基質液を添加し、３７℃で６０分間反応させた。反応開始後０分から６０分まで５分ごとに、マイクロプレートリーダー　ＦｌｅｘＳｔａｔｉｏｎ　３（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ）で、反応液の蛍光強度（ＲＦＵ）（Ｅｘ／Ｅｍ＝３３５ｎｍ／４９５ｎｍ）を測定した。ｎ＝２で反応を行い、反応液の蛍光強度の平均値を測定値とした。
評価における各被験化合物の濃度（最終濃度）は、表１の通りとして実施した。 <Examples 1 and 2 and Comparative Example 1>
(Evaluation of compounds having β-secretase inhibitory activity)
Materials and Methods Test compounds were tested for β-secretase inhibitory activity. As test compounds, cycloleucylalanine (Cyclo(Leu-Ala)) (Comparative Example 1) and cycloleucylglutamate (Cyclo(Leu-Glu)) (Examples 1 and 2) were used. Cyclo (Leu-Ala) was purchased from Bachem, and Cyclo (Leu-Glu) was purchased from Peptide Institute.
In both cases, a commercially available kit, Beta Secretase (BACE1) Activity Assay Kit (abcam), was used to evaluate the β-secretase inhibitory activity. The inhibitory effect on β-secretase enzymatic activity was evaluated according to the method described in the kit.
After mixing the sample solution (test compound solution) and the enzyme solution on a 96 Well Plate (Corning), the mixture was preincubated at 37°C for 10 minutes. After that, a substrate solution was added and reacted at 37° C. for 60 minutes. The fluorescence intensity (RFU) (Ex/Em=335 nm/495 nm) of the reaction solution was measured with a microplate reader FlexStation 3 (Molecular Devices) every 5 minutes from 0 to 60 minutes after the start of the reaction. The reaction was performed with n=2, and the average fluorescence intensity of the reaction solution was used as the measured value.
The concentration (final concentration) of each test compound in the evaluation was carried out as shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
酵素活性の評価には反応液のΔ蛍光強度（反応終了時の蛍光強度（６０分）－反応開始前蛍光強度（０分））を使用した。被験化合物非添加群をＣｏｎｔｒｏｌとした。各被験化合物の阻害活性は、Ｃｏｎｔｒｏｌの酵素活性（Δ蛍光強度）を１として評価を行った。 The Δ fluorescence intensity of the reaction solution (fluorescence intensity at the end of the reaction (60 minutes)−fluorescence intensity before the start of the reaction (0 minutes)) was used to evaluate the enzyme activity. A group to which no test compound was added was used as a control. The inhibitory activity of each test compound was evaluated with the enzyme activity (Δ fluorescence intensity) of Control as 1.
結果
図１は、被験化合物のβ－セクレターゼ（ＢＡＣＥ）阻害活性を示すグラフである。
結果は、平均±標準偏差（ｎ＝２）で示した。図１に示すＢＡＣＥ活性は、ＣｏｎｔｒｏｌのＢＡＣＥ活性（ＣｏｎｔｒｏｌのΔ蛍光強度）を１とした場合の、被験化合物のＢＡＣＥ活性（被験化合物を添加した反応液のΔ蛍光強度）の相対値である。
比較例１として測定したシクロロイシルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ））では阻害活性が確認されなかったが、シクロロイシルグルタメート（Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ））（実施例１、２）について、β－セクレターゼの酵素活性の低下が確認された。
以上の結果より、環状ジペプチドであるＣｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）がβ－セクレターゼ阻害活性を有していることが明らかになった。
β－セクレターゼの阻害により、認知機能低下の原因となるアミロイドβの産生を抑制及び／又は蓄積を抑制することができるため、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）及びその塩が、認知機能の低下抑制又は改善に有効であると考えられる。
 
 
 

  Results FIG. 1 is a graph showing the β-secretase (BACE) inhibitory activity of test compounds.
Results are shown as mean±standard deviation (n=2). The BACE activity shown in FIG. 1 is a relative value of the BACE activity of the test compound (Δ fluorescence intensity of the reaction solution to which the test compound was added) when the BACE activity of Control (Δ fluorescence intensity of Control) is 1.
No inhibitory activity was confirmed in cycloleucylalanine (Cyclo(Leu-Ala)) measured as Comparative Example 1, but cycloleucylglutamate (Cyclo(Leu-Glu)) (Examples 1 and 2) - A decrease in secretase enzymatic activity was observed.
From the above results, it was revealed that the cyclic dipeptide Cyclo(Leu-Glu) has β-secretase inhibitory activity.
By inhibiting β-secretase, it is possible to suppress the production and / or accumulation of amyloid β that causes cognitive function decline, so Cyclo (Leu-Glu) and its salts suppress or improve cognitive function decline. It is considered to be effective for

Claims (8)

  1. Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩を有効成分として含む、認知機能の低下抑制又は改善用組成物。 A composition for suppressing or improving cognitive function, comprising Cyclo(Leu-Glu) or a salt thereof as an active ingredient.
  2. アミロイドβの産生及び／又は蓄積を抑制する、請求項１に記載の組成物。 The composition according to claim 1, which suppresses the production and/or accumulation of amyloid β.
  3. β－セクレターゼを阻害することによりアミロイドβの産生及び／又は蓄積を抑制する、請求項１又は２に記載の組成物。 3. The composition according to claim 1, which suppresses the production and/or accumulation of amyloid β by inhibiting β-secretase.
  4. 前記組成物が、経口用である、請求項１又は２に記載の組成物。 3. The composition according to claim 1 or 2, wherein said composition is for oral use.
  5. 前記組成物が、飲食品又は医薬品である、請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, wherein the composition is a food or drink or a pharmaceutical.
  6. 前記組成物が、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」及び「論理的思考力を維持・改善する」からなる群より選択される１又は２以上の機能の表示を付されたものである、請求項１又は２に記載の組成物。 The composition "enhances cognitive function", "suppresses decline in cognitive function", "maintains good cognitive function", "enhances memory", "suppresses decline in memory", "maintains good memory" , "Improve memory accuracy", "Prevent memory impairment", "Improve memory impairment", "Maintain memory which is a part of cognitive function", "For those who are concerned about memory decline" "improve memory accuracy and judgment accuracy", "improve memory retention or consolidation", "maintain enhanced cognitive function", "executive function" "improve attention and concentration", "improve learning ability", "maintain and improve orientation", "delay age-related cognitive decline", "short-term and long-term labeled with one or more functions selected from the group consisting of "strengthening memory," "promoting verbal and visuospatial memory," and "maintaining/improving logical thinking ability." 3. The composition of claim 1 or 2, wherein the composition is
  7. 認知機能の低下抑制又は改善用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。 Use of Cyclo(Leu-Glu) or a salt thereof in the production of a composition for suppressing or improving cognitive function decline.
  8. 認知機能の低下抑制又は改善のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｇｌｕ）又はその塩の使用。

          Use of Cyclo(Leu-Glu) or a salt thereof for suppressing or improving cognitive function.
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