Composition for suppressing or ameliorating deterioration of cognitive function, and composition for inhibiting β-secretase

Abstract

The purpose of the present invention is to provide: a novel composition for suppressing or ameliorating the deterioration of cognitive function; and a composition for inhibiting β-secretase. The present invention relates to a composition for suppressing or ameliorating the deterioration of cognitive function, the composition containing at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn) or a salt thereof.

Description

Composition for preventing or improving cognitive decline and composition for inhibiting β-secretase

[0001] The present invention relates to a composition for suppressing or improving cognitive decline, a composition for inhibiting β-secretase, and the like.

[0002] Amyloid beta (Aβ) is a type of protein produced in the brain. When Aβ aggregates and forms oligomers or fibrils, it exhibits neurotoxicity. Furthermore, aggregated Aβ accumulates without being excreted from the brain, which is thought to trigger the onset of Alzheimer's disease. Aβ is produced by two-stage cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. It has been reported that BACE1 activity and expression are elevated in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (Non-Patent Document 1). It has also been reported that inhibition of BACE1 suppresses Aβ accumulation in the early stages of Aβ accumulation (Non-Patent Document 2). Therefore, inhibiting BACE1 or suppressing Aβ production or accumulation is thought to be effective, for example, in preventing cognitive decline and Alzheimer's disease.

[0003] Patent Document 1 discloses an agent for suppressing and / or improving the decline in cognitive function of a subject, which contains Cyclo(Gly-Pro). Patent Document 2 discloses a composition for preventing neurological diseases, which contains a heat-treated animal or plant peptide as an active ingredient. Patent Document 3 discloses a composition for preventing neurological diseases, which contains a cyclic dipeptide or a salt thereof having amino acids as its constituent units as an active ingredient, and discloses cyclolysyl lysine [Cyclo(Lys-Lys)] as a specific cyclic dipeptide. However, neither document discusses the suppression of Aβ accumulation or the inhibitory activity of BACE1.

[0004] JP 2020-196686 A International Publication No. 2017 / 119476 International Publication No. 2017 / 119481

[0005] Cheng et al. , Am. J. Pathol. 2014; 184(1): 141-147. Peters et al. , Acta Neuropathol. 2018; 135(5): 695-710.

[0006] An object of the present invention is to provide a novel composition for preventing or ameliorating cognitive decline and a novel composition for inhibiting β-secretase.

[0007] The present inventors have conducted extensive research in light of the above-mentioned problems and have found that cyclic dipeptides, such as Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or salts thereof, inhibit β-secretase. Furthermore, the inventors have found that the above-mentioned cyclic dipeptides or salts thereof inhibit β-secretase, thereby suppressing the production and / or accumulation of amyloid β.

[0008] Furthermore, the present inventors have discovered that cyclic dipeptides, Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), or salts thereof, inhibit β-secretase, thereby suppressing the production and / or accumulation of amyloid β and are effective in suppressing or improving decline in cognitive function, thereby completing the present invention.

[0009] That is, the present invention relates to the following compositions for suppressing or ameliorating cognitive decline, but is not limited thereto: [1] A composition for suppressing or ameliorating cognitive decline, comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof. [2] The composition according to [1] above, further comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof. [3] The composition according to [1] or [2] above, which suppresses the production and / or accumulation of amyloid β. [4] The composition according to any one of [1] to [3] above, which inhibits β-secretase and thereby suppresses the production and / or accumulation of amyloid β. [5] A composition for inhibiting β-secretase, comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or a salt thereof. [6] The composition according to [5] above, which inhibits β-secretase and thereby suppresses the production and / or accumulation of amyloid β. [7] The composition according to any one of [1] to [6] above, which is an oral composition. [8] The composition according to any one of [1] to [7] above, which is a food or drink or an oral pharmaceutical.[9] The composition according to any one of [1] to [8] above, which is labeled with one or more functions selected from the group consisting of "enhancing cognitive function," "suppressing cognitive decline," "maintaining good cognitive function," "enhancing memory," "suppressing memory decline," "maintaining good memory," "enhancing memory accuracy," "preventing memory impairment," "improving memory impairment," "maintaining memory, which is part of cognitive function," "function suitable for those concerned about memory decline," "improving memory accuracy and judgment accuracy, which are part of cognitive function," "improving memory retention or consolidation," "maintaining enhanced cognitive function," "improving executive function," "promoting attention and concentration," "improving learning ability," "maintaining or improving orientation," "delaying age-related cognitive decline," "strengthening short-term and long-term memory," "promoting verbal and visuospatial memory," and "maintaining or improving logical thinking ability."

[0010] According to the present invention, a novel composition for suppressing or ameliorating cognitive decline and a novel composition for inhibiting β-secretase can be provided.

[0011] The composition for preventing or improving cognitive decline of the present invention (also referred to as the "first composition of the present invention") comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof. The first composition of the present invention typically comprises the cyclic dipeptide or a salt thereof as an active ingredient. Preferably, the first composition of the present invention further comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof.

[0012] The β-secretase inhibiting composition of the present invention (also referred to as the "second composition of the present invention") comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or a salt thereof. The second composition of the present invention typically comprises the cyclic dipeptide or a salt thereof as an active ingredient.

[0013] The above Cyclo(Arg-Phe) (cycloarginylphenylalanine), Cyclo(Arg-Tyr) (cycloarginyltyrosine), Cyclo(Glu-Leu) (cycloglutamate-leucine), Cyclo(His-Phe) (cyclohistidinylphenylalanine), Cyclo(Phe-Trp) (cyclophenylalanyltryptophan), Cyclo(Trp-Asn) (cyclotryptophanylasparagine), Cyclo(Hyp-Ala) (cyclohydroxyprolinylalanine), and Cyclo(Leu-Lys) (cycloleucinyllysine) are all cyclic dipeptides. As used herein, the term "cyclic dipeptide" refers to a compound characterized by having amino acids as its constituent units, and having a diketopiperazine structure formed by dehydration condensation of the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. As used herein, the order in which the amino acids are listed does not matter as long as the cyclic dipeptides have the same amino acid structure; for example, Cyclo(Arg-Phe) and Cyclo(Phe-Arg) (cyclophenylalanylarginine) represent the same cyclic dipeptide. Each of the above cyclic dipeptides may be in the form of a salt.

[0014] The salt of the cyclic dipeptide is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for use in foods and beverages, and may be either an acidic salt or a basic salt. Examples of acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, and propionate. Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.

[0015] The origin and production method of the above-mentioned cyclic dipeptides or salts thereof are not particularly limited. Each cyclic dipeptide can be produced according to known methods. Each cyclic dipeptide may be derived from a natural product, artificially synthesized, produced by enzymatic or microbial fermentation methods, or synthesized by dehydrating and cyclizing a linear dipeptide. For example, a heat-treated peptide rich in each of the above-mentioned cyclic dipeptides, such as Cyclo(Arg-Phe), can be obtained by heating a protein hydrolyzate, such as collagen hydrolyzate. Each of the above-mentioned cyclic dipeptides may be incorporated into a composition using a protein hydrolyzate or a heat-treated product thereof containing the cyclic dipeptide. Alternatively, a concentrate, dried powder, or a highly purified form of the protein hydrolyzate or a heat-treated product thereof may be incorporated into a composition. The first and second compositions of the present invention may contain, for example, a protein hydrolyzate or a heat-treated product thereof, and each of the above-mentioned cyclic dipeptides may be part of the protein hydrolyzate or a heat-treated product thereof. Each of the above-mentioned cyclic dipeptides may also be commercially available. A salt of a cyclic dipeptide can be easily prepared by those skilled in the art using any method known in the art.

[0016] The first and second compositions of the present invention preferably inhibit the production and / or accumulation of amyloid β. Aβ is a peptide that is sometimes called amyloid β protein, amyloid β peptide, or β-amyloid. Aβ is typically a peptide consisting of around 40 amino acids, and examples include amyloid β1-38, amyloid β1-40, and amyloid β1-42.

[0017] Unassociated Aβ is sometimes called amyloid β monomer. Aβ may form aggregates of two or more molecules. Aβ may form soluble aggregates (amyloid β oligomers) in which two or more Aβ molecules (e.g., 2 to 50 molecules) are aggregated. Examples of amyloid β oligomers include amyloid β1-38 oligomers, amyloid β1-40 oligomers, and amyloid β1-42 oligomers. Aβ in the present invention includes unassociated Aβ and Aβ that has formed aggregates such as oligomers.

[0018] The amyloid β is preferably at least one selected from the group consisting of amyloid β1-38, amyloid β1-40, and amyloid β1-42.

[0019] The first and second compositions of the present invention can be used to inhibit the production and / or accumulation of amyloid β in the brain.

[0020] In one aspect, the first and second compositions of the present invention can be used for preventing or ameliorating conditions or diseases associated with the production and / or accumulation of amyloid-β, preferably conditions or diseases associated with the production and / or accumulation of amyloid-β in the brain. Examples of such conditions or diseases include conditions or diseases accompanied by or caused by the production and / or accumulation of amyloid-β. Examples of conditions or diseases accompanied by or caused by the production and / or accumulation of amyloid-β in the brain include Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment (functional impairment), and age-related cognitive impairment (functional impairment). The first and second compositions of the present invention can be used for preventing or ameliorating the above-mentioned conditions or diseases. As used herein, "preventing a condition or disease" includes preventing the onset, delaying the onset, reducing the incidence, reducing the risk of onset, etc. Amelioration of a condition or disease includes causing a subject to recover from the condition or disease, alleviating the symptoms of the condition or disease, reversing the symptoms of the condition or disease, slowing or preventing the progression of the condition or disease, etc. Recovery includes partial recovery.

[0021] Cognitive function is known to decline in Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment. Symptoms of cognitive decline in Alzheimer's disease, mild cognitive impairment, and age-related cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficulty naming things), apraxia, agnosia (getting lost in familiar places, etc.), disorientation (the ability to correctly recognize one's situation, such as place, time, and people's names), decline in verbal and non-verbal learning ability, decline in auditory and visual processing, decline in executive function, executive dysfunction (inability to plan and execute), decline in concentration, decline in attention, decline in judgment, decline in spatial awareness, decline in cognitive flexibility, decline in information processing speed, and decline in logical thinking. Suppressing the production and / or accumulation of amyloid beta is believed to have the effect of suppressing or ameliorating cognitive decline, for example, the effect of suppressing or ameliorating the above-mentioned symptoms. In one aspect, the first and second compositions of the present invention can be used to prevent or ameliorate conditions or diseases associated with cognitive decline.

[0022] The first composition of the present invention inhibits or improves cognitive decline. Preferably, the first composition of the present invention inhibits or improves cognitive decline caused by Alzheimer's disease, mild cognitive impairment, or age-related cognitive impairment. In the present invention, inhibiting or improving cognitive decline includes inhibiting further symptomatic decline (worsening) of "cognitive function," i.e., maintaining cognitive function, delaying cognitive decline (worsening), and improving cognitive function that has once declined (worsened). Furthermore, "cognitive function" refers to brain functions such as memory function, learning ability, memory consolidation, executive function, attention (attention function), and concentration. The cognitive impairment refers to the inability of some or all of the cognitive functions to function.

[0023] The β-secretase (BACE1) inhibited by the β-secretase inhibitory composition of the second invention is an aspartyl protease that plays a major role in generating amyloid beta (Aβ) peptide from amyloid precursor protein (APP). Therefore, inhibiting the activity of β-secretase can suppress the production and / or accumulation of amyloid beta. The composition of the second invention can be used to inhibit β-secretase in the brain. The composition of the first invention can also be used to inhibit β-secretase in the brain.

[0024] The first and second compositions of the present invention preferably inhibit β-secretase to suppress the production and / or accumulation of amyloid β. The first and second compositions of the present invention can be used to suppress the production and / or accumulation of amyloid β by inhibiting β-secretase in the brain. Furthermore, the first and second compositions of the present invention preferably inhibit β-secretase to suppress the production and / or accumulation of amyloid β, thereby suppressing or ameliorating cognitive decline. The first and second compositions of the present invention preferably inhibit β-secretase to suppress the production and / or accumulation of amyloid β, thereby suppressing or ameliorating cognitive decline.

[0025] The first and second compositions of the present invention can be used for either therapeutic (medical) or non-therapeutic (non-medical) purposes. Non-therapeutic refers to a concept that does not include medical procedures, i.e., surgery, treatment, or diagnosis of humans. The first and second compositions of the present invention can be provided in the form of a drug, for example, but are not limited to this form. The drug can also be provided as a composition itself, or as a composition containing the drug. In one aspect, the first composition of the present invention can also be referred to as a cognitive decline inhibitor or a cognitive decline ameliorator. The second composition of the present invention can also be referred to as a β-secretase inhibitor. The first and second compositions of the present invention can also be referred to as an amyloid β production inhibitor or an amyloid β accumulation inhibitor, respectively.

[0026] The first and second compositions of the present invention may be for oral or parenteral use. The first and second compositions of the present invention are preferably oral compositions. The first and second compositions of the present invention may be in the form of, for example, a food or drink, a pharmaceutical product, a quasi-drug, a feed, etc., preferably a food or drink or a pharmaceutical product, and more preferably a food or drink or an oral pharmaceutical product. The composition of the present invention can also be used by adding it to a food or drink, a pharmaceutical product, a quasi-drug, a feed, etc. The form of the composition of the present invention is not particularly limited and may be any of a solid form (e.g., powder, granules, tablet, etc.), a liquid form, a paste, etc.

[0027] The compositions of the first and second inventions may further contain various diluents, acidulants, antioxidants, stabilizers, preservatives, flavorings, emulsifiers, colorants, seasonings, pH adjusters, nutritional enhancers, etc. that are permitted as additives to foods, beverages, pharmaceuticals, etc.

[0028] For example, when the first and second compositions of the present invention are used as foods and beverages, ingredients usable for foods and beverages (e.g., food materials, food additives used as needed, etc.) can be blended with the cyclic dipeptide or its salt contained in the first and second compositions of the present invention to produce various foods and beverages. The foods and beverages are not particularly limited, and examples include general foods and beverages, health foods, functional foods, foods for specified health uses, health supplements, and foods for patients. The health foods, functional foods, foods for specified health uses, health supplements, and the like can be used in various dosage forms, such as liquids, fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, and liquid diets.

[0029] When the compositions of the first and second aspects of the present invention are used as pharmaceuticals or quasi-drugs, pharmacologically acceptable carriers and additives, if necessary, can be added to the cyclic dipeptide or salt thereof contained in the compositions of the first and second aspects of the present invention to produce pharmaceuticals or quasi-drugs in various dosage forms. Such carriers, additives, etc. may be any pharmacologically acceptable carriers that can be used in pharmaceuticals or quasi-drugs, and examples thereof include one or more of excipients, binders, disintegrants, lubricants, antioxidants, colorants, etc. The pharmaceuticals or quasi-drugs may be administered orally or parenterally (transdermally, transmucosally, enterally, by injection, etc.). When the compositions of the first and second aspects of the present invention are used as pharmaceuticals or quasi-drugs, oral pharmaceuticals or oral quasi-drugs are preferred. Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewable tablets, etc. Dosage forms for parenteral administration include, for example, injections, drip infusions, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants), etc. The pharmaceutical product may be a pharmaceutical product for non-human animals.

[0030] When the first and second compositions of the present invention are used as feed, the cyclic dipeptide or a salt thereof contained in the first and second compositions of the present invention may be blended into the feed. Feed also includes feed additives. Examples of feed include livestock feed for cows, pigs, chickens, sheep, horses, etc.; small animal feed for rabbits, rats, mice, etc.; and pet food for dogs, cats, small birds, etc.

[0031] When the compositions of the first and second present inventions are used, for example, as foods and beverages, pharmaceuticals, quasi-drugs, feeds, etc., the method for producing them is not particularly limited, and they can be produced by a general method using the above-mentioned cyclic dipeptide or a salt thereof contained in the compositions of the first and second present inventions.

[0032] In one embodiment, the compositions of the first and second inventions are preferably liquid compositions, and more preferably beverages. The beverage may be, for example, a functional beverage. The form of the beverage is not particularly limited, and may be a packaged beverage. The container for the packaged beverage is not particularly limited, and any container of any form or material may be used. For example, any commonly used container may be used, such as metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; paper containers such as paper cartons; glass containers such as glass bottles; and wooden containers such as barrels. A packaged beverage can be obtained by filling and sealing such a container with the beverage.

[0033] The total content of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), and a salt thereof, contained in the composition of the first present invention is not particularly limited, and can be set depending on the form of the composition, etc.

[0034] Furthermore, when the composition of the first invention further contains at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), the total content of the cyclic dipeptide and the salt thereof in the composition is not particularly limited and can be set depending on the form, etc.

[0035] The total content of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), and a salt thereof, contained in the composition of the second present invention is not particularly limited, and can be set depending on the form of the composition, etc.

[0036] When the compositions of the first and second aspects of the present invention contain Cyclo(Arg-Phe) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Arg-Phe) or a salt thereof, the content of Cyclo(Arg-Phe) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.001 wt % or more, preferably 0.005 wt % or more, more preferably 0.01 wt % or more, and preferably 50 wt % or less, more preferably 20 wt % or less, even more preferably 10 wt % or less, and even more preferably 5 wt % or less, in terms of the free cyclic dipeptide. In one aspect, the content of Cyclo(Arg-Phe) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.001 to 50 wt % in terms of the free cyclic dipeptide. The content is more preferably 0.005 to 20% by weight, and even more preferably 0.01 to 10% by weight.

[0037] When the compositions of the first and second aspects of the present invention contain Cyclo(Arg-Tyr) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Arg-Tyr) or a salt thereof, the content of Cyclo(Arg-Tyr) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.0005% by weight or more, preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.5% by weight or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Arg-Tyr) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.0005 to 5% by weight, calculated as the free cyclic dipeptide. The content is more preferably 0.001 to 1% by weight, and even more preferably 0.005 to 0.5% by weight.

[0038] When the compositions of the first and second aspects of the present invention contain Cyclo(Glu-Leu) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Glu-Leu) or a salt thereof, the content of Cyclo(Glu-Leu) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.001% by weight or more, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Glu-Leu) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.001 to 20% by weight, calculated as the free cyclic dipeptide. The content is more preferably 0.005 to 10% by weight, and even more preferably 0.01 to 5% by weight.

[0039] When the compositions of the first and second aspects of the present invention contain Cyclo(His-Phe) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(His-Phe) or a salt thereof, the content of Cyclo(His-Phe) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.0005% by weight or more, preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.5% by weight or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(His-Phe) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.0005 to 5% by weight, calculated as the free cyclic dipeptide. The content is more preferably 0.001 to 1% by weight, and even more preferably 0.005 to 0.5% by weight.

[0040] When the compositions of the first and second aspects of the present invention contain Cyclo(Phe-Trp) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Phe-Trp) or a salt thereof, the content of Cyclo(Phe-Trp) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.0001 wt % or more, preferably 0.0005 wt % or more, more preferably 0.001 wt % or more, and preferably 5 wt % or less, more preferably 1 wt % or less, and even more preferably 0.1 wt % or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Phe-Trp) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.0001 to 5 wt % in terms of the free cyclic dipeptide. The content is more preferably 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight.

[0041] When the compositions of the first and second aspects of the present invention contain Cyclo(Trp-Asn) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Trp-Asn) or a salt thereof, the content of Cyclo(Trp-Asn) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.0001 wt % or more, preferably 0.0005 wt % or more, more preferably 0.001 wt % or more, and preferably 5 wt % or less, more preferably 1 wt % or less, and even more preferably 0.1 wt % or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Trp-Asn) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.0001 to 5 wt % in terms of the free cyclic dipeptide. The content is more preferably 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight.

[0042] When the compositions of the first and second aspects of the present invention contain Cyclo(Hyp-Ala) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Hyp-Ala) or a salt thereof, the content of Cyclo(Hyp-Ala) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.0001 wt % or more, preferably 0.0005 wt % or more, more preferably 0.001 wt % or more, and preferably 5 wt % or less, more preferably 1 wt % or less, and even more preferably 0.1 wt % or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Hyp-Ala) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.0001 to 5 wt % in terms of the free cyclic dipeptide. The content is more preferably 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight.

[0043] When the compositions of the first and second aspects of the present invention contain Cyclo(Leu-Lys) or a salt thereof, the content thereof is not particularly limited and can be set depending on the form, etc. In one aspect, when the compositions of the first and second aspects of the present invention contain Cyclo(Leu-Lys) or a salt thereof, the content of Cyclo(Leu-Lys) or a salt thereof in the compositions of the first and second aspects of the present invention may be, for example, 0.001% by weight or more, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less, calculated as the free cyclic dipeptide. In one aspect, the content of Cyclo(Leu-Lys) or a salt thereof in the compositions of the first and second aspects of the present invention is, for example, preferably 0.001 to 20% by weight, calculated as the free cyclic dipeptide. The content is more preferably 0.005 to 10% by weight, and even more preferably 0.01 to 5% by weight.

[0044] The total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and salts thereof in the composition of the first present invention is not particularly limited, and can be set depending on the form, etc. In one embodiment, the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), and salts thereof, calculated as the free cyclic dipeptide, may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, and even more preferably 0.01% by weight or more, and is preferably 50% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and even more preferably 10% by weight or less. In one embodiment, the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), and salts thereof, calculated as the free cyclic dipeptide, in the composition of the first present invention may be, for example, 0.0001 to 50 wt %, preferably 0.0005 to 30 wt %, more preferably 0.001 to 20 wt %, and even more preferably 0.01 to 10 wt %.

[0045] Furthermore, when the composition of the first invention further comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) or a salt thereof, the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), and salts thereof in the compositions of the first and second inventions is not particularly limited and can be set depending on the form, etc. In one aspect, the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), and salts thereof, in terms of free cyclic dipeptide, may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, even more preferably 0.01% by weight or more, and preferably 50% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and even more preferably 10% by weight or less. In one embodiment, the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), and salts thereof, calculated as free cyclic dipeptides, may be, for example, 0.0001 to 50 wt %, preferably 0.0005 to 30 wt %, more preferably 0.001 to 20 wt %, and even more preferably 0.01 to 10 wt %, in the composition of the first present invention.

[0046] Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), and salts thereof can be quantified by a known method, for example, liquid chromatography mass spectrometry (LC-MS / MS). When two or more types of the cyclic dipeptide or salts thereof are contained, the total content of the cyclic dipeptide or salt thereof is the total amount of the cyclic dipeptide or salts thereof. The following measurement conditions can be used for LC-MS / MS measurement. As the apparatus, for example, an Agilent 1290 binary LC coupled with an AB Sciex 5600+ TripleTOF system can be used. LC column: CORTECS T3 Column, 120 Å, 1.6 μm, 2.1 mm × 100 mm (Waters Corporation) Sample injection volume: 5 μL Column temperature: 40°C (LC chromatographic conditions) Mobile phase: Solution A: Water containing 0.1% formic acid Solution B: Acetonitrile containing 0.1% formic acid Gradient (solution B concentration): 0 to 1 min: Solution B 1% 1 to 8.5 min: Solution B 1% → 40% 8.5 to 13 min: Solution B 40% → 90% 13 to 15.5 min: Solution B 90% → 100% 15.5 to 17.8 min: Solution B 100% 17.8 to 18 min: Solution B 100% → 1% 18 to 20 min: Solution B 1%

[0047] The first and second compositions of the present invention are preferably taken orally (administered orally). The dosage (which can also be referred to as intake amount) of the first and second compositions of the present invention is not particularly limited. The dosage of the first composition of the present invention may be an amount that achieves an effect of inhibiting or improving cognitive decline, for example, an amount that achieves an effect of inhibiting or improving cognitive decline by suppressing the production and / or accumulation of amyloid beta. Furthermore, for example, the dosage may be an amount that achieves an effect of inhibiting or improving cognitive decline by inhibiting the production and / or accumulation of amyloid beta through the inhibition of beta-secretase. Furthermore, as long as these effects are achieved, the dosage may be appropriately determined depending on the dosage form, administration method, subject weight, etc. The dosage of the second composition of the present invention may be an amount that achieves an inhibitory effect on beta-secretase, for example, an amount that achieves an effect of inhibiting the production and / or accumulation of amyloid beta through the inhibition of beta-secretase. Furthermore, for example, the dosage may be an amount that achieves an effect of inhibiting or improving cognitive decline by inhibiting the production and / or accumulation of amyloid beta. Furthermore, the amount may be appropriately determined depending on the dosage form, administration method, subject weight, etc., so long as these effects are obtained.

[0048] In one embodiment, when the composition of the first invention is ingested or administered to a human (adult) subject, the dosage is preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and also preferably 5000 mg or less, more preferably 3000 mg or less, even more preferably 2000 mg or less per day, as the total dosage (in terms of free cyclic dipeptides) of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and salts thereof. In one embodiment, when the composition of the first invention is ingested or administered to a human (adult), the total dosage of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and their salts (calculated as free cyclic dipeptides) is preferably 0.001 to 5,000 mg, more preferably 0.01 to 3,000 mg, and even more preferably 0.1 to 2,000 mg per day. Furthermore, when the composition of the first invention further comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) or a salt thereof, the dosage of the composition of the first invention when ingested or administered to a human (adult) can be as follows:

[0049] In one embodiment, when the first and second compositions of the present invention are ingested or administered to a human (adult) subject, the dosage is preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and also preferably 5000 mg or less, more preferably 3000 mg or less, even more preferably 2000 mg or less per day as the total dosage (in terms of free cyclic dipeptides) of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys) and salts thereof. In one embodiment, when the first or second compositions of the present invention are ingested or administered to a human (adult), the total dosage of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), and salts thereof, is preferably 0.001 to 5000 mg, more preferably 0.01 to 3000 mg, and even more preferably 0.1 to 2000 mg per day. It is preferable to ingest or administer the above amount once or more times a day, for example, once a day or divided into several times (e.g., 2 to 3 times a day). In one embodiment, it is preferable to orally ingest or administer the above amount of the cyclic dipeptide or salt thereof. In the case of a human (adult), it is preferable to ingest or administer the above amount of the cyclic dipeptide or a salt thereof per 60 kg of body weight per day. In one embodiment, the first and second compositions of the present invention may be oral compositions for ingesting or administering the above amount of the cyclic dipeptide or a salt thereof per 60 kg of body weight per day to a human.

[0050] The compositions of the first and second inventions are preferably ones that are continuously ingested or administered. In the first invention, it is expected that a greater effect can be obtained by continuously ingesting or administering at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn). In the second present invention, it is expected that a greater effect can be obtained by continuously ingesting or administering at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys). In one embodiment, the compositions of the first and second present inventions are preferably continuously ingested or administered for preferably one week or more, more preferably four weeks or more, and even more preferably eight weeks or more. The above-mentioned cyclic dipeptide or a salt thereof can be ingested as a food or drink, and from the viewpoint of safety, it is considered that there are few problems with, for example, long-term ingestion.

[0051] The subject (which may also be referred to as the administration subject) to whom the first and second compositions of the present invention are administered or ingested is not particularly limited. The subject is preferably a human or a non-human mammal, and more preferably a human. In one embodiment, the subjects to whom the first and second compositions of the present invention are administered include subjects who require or desire suppression or improvement of cognitive decline, subjects who require or desire prevention or improvement of a condition or disease associated with cognitive decline, subjects who require or desire β-secretase inhibition, subjects who require or desire prevention or improvement of a condition or disease associated with β-secretase production, subjects who require or desire suppression of amyloid β production and / or accumulation, and subjects who require or desire prevention or improvement of a condition or disease associated with amyloid β production and / or accumulation. In one embodiment, the subjects to whom the first and second compositions of the present invention are administered include middle-aged and elderly individuals. Middle-aged and elderly individuals include elderly individuals. Middle-aged and elderly individuals may be, for example, individuals aged 40 or older. In one embodiment, among middle-aged and elderly individuals, elderly individuals are preferred. Elderly individuals may be, for example, individuals aged 60 or older or 65 or older. In one embodiment, the subjects to whom the first composition of the present invention is administered may be healthy individuals. For example, it can be used in healthy individuals for the purposes of inhibiting or improving cognitive function decline, inhibiting the production and / or accumulation of amyloid β in the brain, preventing the production and / or accumulation of amyloid β in the brain, preventing Alzheimer's disease, mild cognitive impairment (functional) or age-related cognitive impairment (functional) and inhibiting β-secretase in the brain. In one embodiment, the subject to which the second composition of the present invention is administered may be a healthy individual. For example, it can be used in healthy individuals for the purposes of inhibiting β-secretase in the brain, inhibiting the production and / or accumulation of amyloid β in the brain, preventing the production and / or accumulation of amyloid β in the brain, preventing Alzheimer's disease, mild cognitive impairment or age-related cognitive impairment, and the like.

[0052] The composition of the first invention may be labeled with a function exhibited by inhibiting or improving cognitive decline. Furthermore, the composition of the second invention may be labeled with a function exhibited by β-secretase inhibition. Such a label is also referred to as a functional label. The label that may be attached to the compositions of the first and second inventions is not particularly limited. Examples of such labels include "enhancing cognitive function," "suppressing cognitive decline," "maintaining good cognitive function," "enhancing memory," "suppressing memory decline," "maintaining good memory," "enhancing memory accuracy," "preventing memory impairment," "improving memory impairment," "maintaining memory, which is part of cognitive function," "function suitable for those concerned about memory decline," "improving memory accuracy and judgment accuracy, which are part of cognitive function," "improving memory retention or integration," "maintaining enhanced cognitive function," "improving executive function," "promoting attention and concentration," "improving learning ability," "maintaining or improving orientation," "delaying age-related cognitive decline," "enhancing short-term and long-term memory," "promoting verbal and visuospatial memory," "maintaining or improving logical thinking," and labels or functional labels that can be considered equivalent thereto. In one aspect of the present invention, the compositions of the first and second aspects of the present invention are preferably foods and beverages to which one or more of the above-mentioned labels are attached. The above-mentioned labels may also be labels indicating that the composition is used to obtain the above-mentioned functions. The labels may be attached to the composition itself, or to the container or packaging of the composition.

[0053] The present invention also encompasses the following methods and uses: A method for suppressing or ameliorating cognitive decline, which comprises administering at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof. Use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof, for suppressing or ameliorating cognitive decline. A method for inhibiting β-secretase, comprising administering at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or a salt thereof. Use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or a salt thereof, for inhibiting β-secretase. The method may be a therapeutic method or a non-therapeutic method. The use may be a therapeutic use or a non-therapeutic use.

[0054] In the above-mentioned methods and uses, the cyclic dipeptide or a salt thereof is preferably ingested or administered to a subject at least once a day, for example, once to several times (e.g., two to three times) a day. The above-mentioned uses are preferably used in humans or non-human mammals, more preferably in humans. In one aspect, Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), or salts thereof can be used to prevent or ameliorate conditions or diseases associated with cognitive decline. Furthermore, Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), or salts thereof can be used to prevent or ameliorate conditions or diseases for which inhibition of β-secretase is effective in preventing or ameliorating them. Furthermore, Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), or salts thereof can be used to prevent or ameliorate conditions or diseases associated with the production and / or accumulation of amyloid beta. The present invention also encompasses methods for preventing or ameliorating conditions or diseases associated with cognitive decline, methods for preventing or ameliorating conditions or diseases for which the inhibition of beta-secretase is effective in preventing or ameliorating, and methods for preventing or ameliorating conditions or diseases associated with the production and / or accumulation of amyloid beta, which involve administering each of the above-mentioned cyclic dipeptides or salts thereof.

[0055] In the above-mentioned methods and uses, the cyclic dipeptide or a salt thereof may be used in an amount (which may also be referred to as an effective amount) that is sufficient to achieve the effect of suppressing or improving cognitive decline, inhibiting β-secretase, or suppressing the production and / or accumulation of amyloid β. The preferred dosage, administration method, and administration target of the cyclic dipeptide or salt thereof are the same as those of the first and second compositions of the present invention described above. The cyclic dipeptide or salt thereof may be ingested or administered as is, or as a composition containing the cyclic dipeptide or salt thereof. For example, the first or second composition of the present invention may be ingested or administered.

[0056] Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), or salts thereof can be used for the production of foods and beverages, pharmaceuticals, quasi-drugs, feeds, etc. used for suppressing or improving cognitive decline. In one aspect, the present invention also encompasses the use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof, in the production of a composition for suppressing or improving cognitive decline. Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), or salts thereof can be used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. that are used for inhibiting β-secretase or suppressing the production and / or accumulation of amyloid β. In one aspect, the present invention also encompasses the use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys), or a salt thereof, in the production of a composition for inhibiting β-secretase or a composition for suppressing the production and / or accumulation of amyloid β.

[0057] In this specification, a numerical range expressed by a lower limit and an upper limit, i.e., "lower limit to upper limit," includes both the lower limit and the upper limit. For example, a range expressed by "1 to 2" means 1 or more and 2 or less, including 1 and 2. In this specification, the upper and lower limits may be any combination of ranges. All academic literature and patent documents described in this specification are incorporated herein by reference.

[0058] The present invention will be explained in more detail below by way of examples, but the scope of the present invention is not limited thereto.

[0059] Example 1 Each cyclic dipeptide was evaluated for its β-secretase (BACE1) inhibitory activity.

[0060] (Materials and Methods) A. Reagents BACE1 Inhibitor Screening Kit (Fluorometric) was obtained from Abcam. Cyclic dipeptides (Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys)) were purchased from Axil Scientific Pte. Other reagents were purchased from Sigma-Aldrich.

[0061] B. BACE1 Inhibition Assay The BACE1 inhibitory activity of each cyclic dipeptide was evaluated using the BACE1 Inhibitor Screening Kit (Fluorometric). The BACE1 inhibition assay was performed according to the kit manufacturer's protocol. Each cyclic dipeptide was dissolved in dimethyl sulfoxide (DMSO) at a 100x (100x) high stock concentration and then diluted with assay buffer to twice the test concentration (2x). The resulting dilutions of each cyclic dipeptide were used in the following experiments. BACE1 enzyme assay mixes were prepared by diluting the stock enzyme (25x) with assay buffer. 50 μL of the resulting diluted enzyme solution was mixed with 50 μL of each cyclic dipeptide dilution and transferred to any well of a flat-bottom 96-well black plate to prepare a reaction mix. Fluorescence (λEx / λEm = 345 / 500 nm) readings of the assay plates were monitored using a Tecan Spark® multimode microplate reader for 30 minutes at 37° C. The relative percent inhibition of each sample was calculated from the fluorescence readings according to the manufacturer's protocol.

[0062] Statistical analysis was performed using GraphPad Prism version 7.0 (San Diego, California, USA). The best-fit IC50 value (hereinafter referred to as IC50) of each cyclic dipeptide was calculated by fitting the concentration and the relative inhibition rate to the equation log(cyclic dipeptide) vs. normalized inhibition rate.

[0063] (Results) Each cyclic dipeptide had the effect of inhibiting BACE 1. The IC50 (μg / mL) of each cyclic dipeptide is shown in Table 1.

[0064]

[0065] Table 2 shows the relative % inhibition of each cyclic dipeptide tested at various concentrations. The mean % BACE1 inhibition values ​​are shown in Table 2 (n=2). The concentration and % relative inhibition values ​​of each cyclic dipeptide were fitted to the log(cyclic dipeptide) vs. normalized inhibition equation to determine experimental IC50 values ​​(Table 1).

[0066]

[0067] BACE1 is an aspartyl protease that plays a key role in generating amyloid beta (Aβ) peptides from amyloid precursor proteins. A strong positive correlation between Aβ peptide concentrations and cognitive function (Reference 1), coupled with evidence of elevated BACE1 activity in Alzheimer's disease models (Reference 2), suggests that BACE1 inhibition is a promising strategy for slowing cognitive decline (Reference 3). Results of BACE1 inhibition assays showed that each cyclic dipeptide could inhibit BACE1 with IC50 values ​​ranging from 28.2 to 430.8 μg / mL (Table 1). Reference 1: Naslund et al., JAMA 2000, 283(12), 1571-1577. Reference 2: Fukumoto et al., Arch. Neurol. 2002, 59(9), 1381-9. Reference 3: McDade et al. , Nature Reviews Neurology 2021, 17(11), 703-714.

Claims

1. A composition for inhibiting or improving decline in cognitive function, comprising at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn).

2. The composition according to claim 1, further comprising at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys).

3. The composition described in claim 1, which inhibits the production and / or accumulation of amyloid beta.

4. The composition according to claim 1, which inhibits the production and / or accumulation of amyloid β by inhibiting β-secretase.

5. A composition for inhibiting β-secretase, comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof.

6. The composition according to claim 5, which inhibits the production and / or accumulation of amyloid β by inhibiting β-secretase.

7. The composition according to any one of claims 1 to 6, which is an oral composition.

8. The composition according to any one of claims 1 to 6, which is a food, drink or oral medicine.

9. The composition according to any one of claims 1 to 6, which is labeled with one or more functions selected from the group consisting of "enhancing cognitive function", "suppressing cognitive decline", "maintaining good cognitive function", "enhancing memory", "suppressing memory decline", "maintaining good memory", "enhancing memory accuracy", "preventing memory impairment", "ameliorating memory impairment", "maintaining memory, which is a part of cognitive function", "function suitable for those concerned about memory decline", "improving memory accuracy and judgment accuracy, which are parts of cognitive function", "improving memory retention or consolidation", "maintaining enhanced cognitive function", "improving executive function", "promoting attention and concentration", "improving learning ability", "maintaining or improving orientation", "delaying cognitive decline associated with aging", "strengthening short-term and long-term memory", "promoting verbal and visuospatial memory" and "maintaining or improving logical thinking ability".