Peptide or salt thereof, composition containing same, and composition for suppressing decline of or improving cognitive functions

Abstract

The purpose of the present invention is to provide: a peptide or a salt thereof which is useful for suppressing the decline of or improving cognitive functions; and a composition for suppressing the decline of or improving cognitive functions. The present invention pertains to a composition containing a peptide consisting of one amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), and IGME (SEQ ID NO: 16), or a salt thereof.

Description

Peptide or salt thereof, composition containing same, and composition for preventing or improving cognitive decline

[0001] The present invention relates to a peptide or a salt thereof, and a composition containing the same. The present invention also relates to a composition for suppressing or improving cognitive decline, etc.

[0002] Improvement of cognitive function, such as memory function, is desired regardless of generation. Furthermore, in recent years, in countries with a high elderly population, such as Japan, age-related cognitive decline has become a problem, and a search has been made for ingredients that can suppress or improve cognitive decline through daily intake as food or beverages. For example, Patent Document 1 describes an agent for suppressing and / or improving cognitive decline in a subject, which contains Cyclo(Gly-Pro).

[0003] Amyloid beta (Aβ) is a type of protein produced in the brain. It has been reported that there is a strong positive correlation between amyloid beta concentration in the brain and cognitive function (Non-Patent Document 1). When amyloid beta aggregates and forms oligomers or fibrils, it exhibits neurotoxicity. Aggregated amyloid beta accumulates without being excreted from the brain, and is thought to trigger the onset of Alzheimer's disease. Therefore, inhibiting the production or accumulation of amyloid beta is useful for preventing or improving the decline in cognitive function.

[0004] Amyloid-β is produced by two-step cleavage of amyloid precursor protein (APP) by β-secretase 1 (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 2). It has also been reported that inhibition of BACE1 suppresses the accumulation of amyloid-β at an early stage (Non-Patent Document 3).

[0005] Japanese Patent Application Laid-Open No. 2020-196686

[0006] Naslund et al. , JAMA 2000, 283(12), 1571-1577. Cheng et al. , Am. J. Pathol. 2014; 184(1): 141-147. Peters et al. , Acta Neuropathol. 2018; 135(5): 695-710.

[0007] An object of the present invention is to provide a peptide or a salt thereof that is useful for suppressing or ameliorating cognitive decline. Another object of the present invention is to provide a composition for suppressing or ameliorating cognitive decline.

[0008] The present inventors have conducted extensive research in light of the above-mentioned problems and have discovered a peptide having the effect of suppressing the production and / or accumulation of amyloid β. The peptide or a salt thereof having the effect of suppressing the production and / or accumulation of amyloid β is useful for suppressing or improving cognitive decline.

[0009] That is, the present invention relates to the following peptides or salts thereof, compositions, etc., but is not limited thereto: [1] A composition comprising a peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), and IGME (SEQ ID NO: 16), or a salt thereof. [2] The composition according to [1] above, which is used for suppressing or improving cognitive decline. [3] The composition according to [1] or [2] above, further comprising a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and further comprising a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof. [4] The composition according to any of [1] to [3] above, further comprising a peptide consisting of an amino acid sequence selected from the group consisting of VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY, or a salt thereof.[5] A composition for suppressing or improving cognitive decline, comprising a peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), IGME (SEQ ID NO: 16), VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY, or a salt thereof. [6] The composition according to [5] above, which suppresses the production and / or accumulation of amyloid beta. [7] The composition according to [5] or [6] above, which inhibits the production and / or accumulation of amyloid beta by inhibiting beta-secretase. [8] The composition according to any of [5] to [7] above, which comprises a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and further comprises a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof. [9] The composition according to any of [5] to [8] above, which comprises a peptide consisting of the amino acid sequence of GVTHNVPIYEGY (SEQ ID NO: 6) or a salt thereof, and which inhibits the accumulation of amyloid beta by activating neprilysin.

[10] The composition according to any one of [5] to [9] above, which comprises a peptide consisting of the amino acid sequence of IGME (SEQ ID NO: 16) or a salt thereof, and which inhibits the accumulation of amyloid β by promoting the phagocytosis of microglial cells.

[11] The composition according to any one of [1] to

[10] above, which is an oral composition.

[12] The composition according to any one of [1] to

[11] above, which is a food or drink product or an oral pharmaceutical product.

[13] The composition according to any one of [1] to

[12] above, wherein the composition is labeled with at least one function 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 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 age-related cognitive decline," "strengthening short-term and long-term memory," "promoting verbal and visuospatial memory," and "maintaining or improving logical thinking ability."

[14] A peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), and IGME (SEQ ID NO: 16), or a salt thereof.

[0010] According to the present invention, it is possible to provide a peptide or a salt thereof that is useful for suppressing or ameliorating cognitive decline. Furthermore, according to the present invention, it is possible to provide a composition for suppressing or ameliorating cognitive decline.

[0011] Figure 1 is a graph showing the results of evaluating the phagocytic activity of microglia (SIM-A9 cells) treated with peptide P16. Figure 2 is a graph showing the results of evaluating the enzymatic activity of neprilysin (NEP) in microglia treated with peptide P6. Figure 3A is a graph showing the results of evaluating the amyloid beta in the culture supernatant of H4 glioma cells (H4-hAPP cells) treated with a peptide mixture. １－３８3B is a graph showing the concentration of amyloid β (Aβ38) in the culture supernatant of H4-hAPP cells treated with the peptide mixture. １－４２ 1 is a graph showing the concentration of (Aβ42).

[0012] The peptide of the present invention or a salt thereof is a peptide consisting of any one of the amino acid sequences selected from the group consisting of GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), LYEGY (SEQ ID NO: 7), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), and IGME (SEQ ID NO: 16), or a salt thereof.

[0013] Unless otherwise specified, the amino acid sequences of peptides herein are represented by the conventional single-letter abbreviations as follows: A: alanine residue, R: arginine residue, N: asparagine residue, D: aspartic acid residue, C: cysteine ​​residue, Q: glutamine residue, E: glutamic acid residue, G: glycine residue, H: histidine residue, I: isoleucine residue, L: leucine residue, K: lysine residue, M: methionine residue, F: phenylalanine residue, P: proline residue, S: serine residue, T: threonine residue, W: tryptophan residue, Y: tyrosine residue, V: valine residue. Herein, pE represents a pyroglutamic acid residue. Pyroglutamic acid (pyro-Glu) is a cyclic amino acid formed by intramolecular dehydration condensation of the γ-carboxyl group and α-amino group of glutamic acid.

[0014] In this specification, the amino acid sequence of a peptide is represented according to the convention of peptide notation, with the N-terminus (amino terminus) at the left and the C-terminus (carboxyl terminus) at the right. Peptides are linear unless otherwise specified. When an amino acid may have optical isomers, the L-amino acid is shown unless otherwise specified.

[0015] In the present invention, the peptide salt 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.

[0016] In the present invention, the origin and production method of the peptide or its salt are not particularly limited. The peptide or its salt of the present invention can be produced according to known methods. The peptide can be produced, for example, by known peptide synthesis methods. When obtaining the peptide of the present invention by chemical synthesis, it can be synthesized using either solid-phase or liquid-phase methods. The synthesized peptide can be purified by conventional purification methods such as reverse-phase high-performance liquid chromatography, chromatography using an ion exchange resin or a highly porous polymer resin, or affinity chromatography. The peptide of the present invention can also be biosynthesized using microorganisms. When biosynthesizing using microorganisms, an expression vector containing a gene encoding the peptide is prepared, and the expression vector is introduced into a host microorganism to obtain a transformant. The transformant is cultured, and the peptide can be purified from the culture. The host microorganism is not particularly limited, and for example, Escherichia coli, yeast, etc. can be used. Separation and purification from the culture can be performed using conventional purification methods. The peptide of the present invention can also be produced by, for example, enzymatic or chemical hydrolysis of a protein containing the amino acid sequence of the peptide. Peptide salts can be easily prepared by those skilled in the art using any method known in the art. Peptides or salts thereof other than the peptides or salts thereof of the present invention can also be produced by known peptide synthesis methods, biosynthesis methods using the above-mentioned microorganisms, and the like.

[0017] The peptide of the present invention or a salt thereof has the effect of suppressing the production and / or accumulation of amyloid β. The peptide of the present invention or a salt thereof can be used to suppress the production and / or accumulation of amyloid β. By suppressing the production and / or accumulation of amyloid β in the brain, cognitive decline can be suppressed or improved. The peptide of the present invention or a salt thereof can be used, for example, to suppress or improve cognitive decline.

[0018] Amyloid β is a peptide that is sometimes called amyloid β protein, amyloid β peptide, or β-amyloid. Amyloid β is usually a peptide consisting of around 40 amino acids. １－４２ , amyloid beta １－４０ , amyloid beta １－３８ and the like. Amyloid β in a non-associated state is sometimes called amyloid β monomer. Amyloid β may form aggregates of two or more. Amyloid β may form, for example, soluble aggregates (amyloid β oligomers) in which two or more amyloid β molecules (for example, 2 to 50 molecules) aggregate. Examples of amyloid β oligomers include amyloid β. １－４２ Oligomers, amyloid beta １－４０ Oligomers, amyloid beta １－３８ The amyloid β in the present invention includes amyloid β in a non-associated state and amyloid β that has formed aggregates such as oligomers.

[0019] Peptides consisting of the amino acid sequences shown in SEQ ID NOs: 1 to 5 and 7 to 15, or salts thereof, have β-secretase inhibitory activity. These peptides or salts thereof can be used to inhibit β-secretase. β-Secretase is the rate-limiting enzyme in amyloid β production, and its cleavage determines the total amount of amyloid β produced. Therefore, by inhibiting β-secretase, it is possible to suppress the production of amyloid β and the accumulation of amyloid β. Peptides consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 5 and 7 to 15, or salts thereof, can be used, for example, to suppress the production and / or accumulation of amyloid β by inhibiting β-secretase.

[0020] A peptide consisting of the amino acid sequence of SEQ ID NO: 6 (GVTHNVPIYEGY) or a salt thereof has the effect of activating neprilysin (NEP). A peptide consisting of the amino acid sequence shown in SEQ ID NO: 6 or a salt thereof can be used to activate neprilysin. As used herein, neprilysin activation includes an increase in the enzymatic activity of neprilysin and an increase in the protein level of neprilysin. Neprilysin is a major enzyme involved in the degradation of amyloid beta in the brain. Neprilysin can degrade not only amyloid beta monomers but also amyloid beta oligomers. Activating neprilysin in the brain can suppress the accumulation of amyloid beta. A peptide consisting of the amino acid sequence shown in SEQ ID NO: 6 or a salt thereof can be used, for example, to suppress the accumulation of amyloid beta by activating neprilysin.

[0021] A peptide consisting of the amino acid sequence of SEQ ID NO: 16 (IGME) or a salt thereof has the effect of promoting the phagocytosis of microglial cells. A peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 or a salt thereof can be used to promote the phagocytosis of microglial cells. Microglial cells are cells of the central nervous system present in the brain. Microglial cells play an important role in maintaining the brain environment, and one of their functions is the phagocytosis of extracellular proteins such as amyloid beta and brain waste products such as damaged cells. Promoting the phagocytosis of microglial cells promotes the removal of amyloid beta. Therefore, promoting the phagocytosis of microglial cells is effective in suppressing the accumulation of amyloid beta. A peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 or a salt thereof can be used, for example, to suppress the accumulation of amyloid beta by promoting the phagocytosis of microglial cells.

[0022] The peptide or a salt thereof of the present invention can be used alone or in the form of a composition containing components other than the peptide or a salt thereof, for example, as a food or drink, a pharmaceutical product, a quasi-drug, a cosmetic, a feed, etc. The food or drink may be, for example, a general food or drink, a health food, a health drink, a food with functional claims, a food for specified health uses, a health supplement, a food for patients, or raw materials thereof.

[0023] A composition containing the peptide of the present invention or a salt thereof also constitutes one aspect of the present invention. The composition of the present invention comprises a peptide consisting of any one of the amino acid sequences selected from the group consisting of GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), LYEGY (SEQ ID NO: 7), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), and IGME (SEQ ID NO: 16), or a salt thereof. The composition may contain one or more of the above peptides or salts thereof. In one aspect, the composition preferably contains two or more of the above peptides or salts thereof. As described above, peptides consisting of the amino acid sequences set forth in SEQ ID NOS: 1 to 16 or salts thereof have the effect of inhibiting the production and / or accumulation of amyloid β. Compositions containing at least one of the peptides or salts thereof can be used, for example, to inhibit the production and / or accumulation of amyloid β. The compositions can be preferably used to inhibit the production and / or accumulation of amyloid β in the brain.

[0024] The content of the peptide of the present invention or a salt thereof in the composition is not particularly limited, and for example, the total content of the peptide or salt thereof can be 0.001 to 50% by weight. The peptide or salt thereof can be quantified by a known method, for example, liquid chromatography mass spectrometry (LC-MS / MS). When two or more types of peptides or salts thereof are contained, the total content of the peptide or salt thereof is the total amount of these. The following measurement conditions can be used for LC-MS / MS measurement. As an apparatus, for example, an Agilent 1290 binary LC coupled with 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%

[0025] Preferably, the composition of the present invention further comprises a peptide or a salt thereof consisting of any one of the amino acid sequences selected from the group consisting of VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY. These peptides or salts thereof have β-secretase inhibitory activity. Therefore, these peptides or salts thereof have the effect of suppressing the production and / or accumulation of amyloid β. These peptides or salts thereof can be used to suppress or improve cognitive decline.

[0026] A composition comprising a peptide consisting of any of the amino acid sequences of SEQ ID NOS: 1 to 5, 7 to 15, 17 to 19, VV, and AY, or a salt thereof, can be used, for example, as a composition for inhibiting β-secretase. The β-secretase is preferably β-secretase 1. A composition comprising the above-mentioned peptide or a salt thereof can be used to inhibit β-secretase, thereby suppressing the production and / or accumulation of amyloid β. In one aspect, the composition of the present invention can be used to inhibit β-secretase, thereby suppressing the production and / or accumulation of amyloid β.

[0027] A composition containing a peptide consisting of the amino acid sequence shown in SEQ ID NO: 6 (GVTHNVPIYEGY) or a salt thereof can be used as a composition for activating neprilysin. A composition containing a peptide consisting of the amino acid sequence shown in SEQ ID NO: 6 or a salt thereof can be used, for example, to activate neprilysin and thereby inhibit the production and / or accumulation of amyloid β.

[0028] A composition containing a peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 (IGME) or a salt thereof can be used as a composition for promoting phagocytosis in microglial cells. A composition containing a peptide consisting of the amino acid sequence shown in SEQ ID NO: 16 or a salt thereof can be used, for example, to suppress the accumulation of amyloid beta by promoting the phagocytosis of microglial cells.

[0029] In one embodiment, the composition of the present invention preferably comprises a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof. In one embodiment, the composition of the present invention preferably comprises a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and more preferably further comprises a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof. Compositions comprising a peptide consisting of the amino acid sequence of SEQ ID NO: 7 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 14 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 21 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 22 or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof can be preferably used, for example, to inhibit the production and / or accumulation of amyloid beta. Cyclo(Trp-Pro) (cyclotryptophanylproline) is a cyclic dipeptide having a structure in which tryptophan (Trp) and proline (Pro) are condensed together. 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 between the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. In this specification, as long as the amino acid structure of the cyclic dipeptide is the same, the order in which they are listed does not matter, and Cyclo(Trp-Pro) and Cyclo(Pro-Trp) (cycloprolyltryptophan) refer to the same cyclic dipeptide.

[0030] In the composition of the present invention, components other than the peptide or salt thereof can be appropriately selected depending on the form of the composition, etc. The total content of the peptide or salt thereof consisting of any of the amino acid sequences of SEQ ID NOS: 1 to 19, VV, and AY in the composition is not particularly limited and can be, for example, 0.001 to 50 wt %. In one aspect, when the composition is a liquid composition such as a beverage, the total content of the peptide or salt thereof is preferably 0.01 to 200 mg / mL, more preferably 0.05 to 100 mg / mL.

[0031] Peptides consisting of any of the amino acid sequences of SEQ ID NOS: 1 to 19, VV, and AY, or salts thereof, have the effect of suppressing the production and / or accumulation of amyloid beta. Therefore, these peptides or salts thereof, and compositions containing them, are useful, for example, for suppressing cognitive decline or improving cognitive function. In one aspect, the compositions of the present invention can be preferably used for suppressing or improving cognitive decline. The compositions of the present invention may, for example, contain one or more of the above-mentioned peptides or salts thereof as active ingredients. Furthermore, the above-mentioned peptides or salts thereof, or compositions containing them, can be used for the prevention or amelioration of conditions or diseases associated with amyloid beta accumulation, preferably conditions or diseases associated with amyloid beta accumulation in the brain. Such conditions or diseases include conditions or diseases accompanied by or caused by amyloid beta accumulation. Conditions or diseases accompanied by or caused by amyloid beta accumulation in the brain include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and age-related cognitive impairment. As used herein, prevention of 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 recovering a subject from a condition or disease, alleviating the symptoms of a condition or disease, improving the symptoms of a condition or disease, delaying or preventing the progression of a condition or disease, etc.

[0032] The present invention also encompasses a composition for preventing or improving cognitive decline. The composition for preventing or improving cognitive decline of the present invention comprises a peptide consisting of any amino acid sequence selected from the group consisting of GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), LYEGY (SEQ ID NO: 7), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), IGME (SEQ ID NO: 16), VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY, or a salt thereof. The composition for suppressing or improving cognitive decline of the present invention usually contains the above-mentioned peptide or a salt thereof as an active ingredient. The composition for suppressing or improving cognitive decline may contain one or more of the above-mentioned peptides or salts thereof. In one aspect, the composition for suppressing or improving cognitive decline preferably contains two or more of the above-mentioned peptides or salts thereof. This is because a higher effect of suppressing or improving cognitive decline can be obtained.

[0033] In one aspect, the composition of the present invention for inhibiting or improving cognitive decline can be used to inhibit cognitive decline or improve cognitive function by inhibiting the production and / or accumulation of amyloid beta.

[0034] In one aspect, the composition for inhibiting or ameliorating cognitive decline of the present invention preferably comprises a peptide consisting of any of the amino acid sequences of SEQ ID NOS: 1 to 5, 7 to 15, 17 to 19, VV, and AY, or a salt thereof. A composition comprising a peptide consisting of any of the above amino acid sequences, or a salt thereof, can inhibit the production and / or accumulation of amyloid beta by inhibiting β-secretase. In one aspect, the composition preferably comprises a peptide consisting of the amino acid sequence of VIQY (SEQ ID NO: 17), or a salt thereof, due to its excellent β-secretase inhibitory activity.

[0035] In one aspect, the composition for suppressing or improving cognitive decline preferably comprises a peptide consisting of the amino acid sequence shown in SEQ ID NO: 17 or a salt thereof, and more preferably the composition further comprises a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 1 to 16, 18 to 19, VV, and AY or a salt thereof.

[0036] In one aspect, the composition for suppressing or ameliorating cognitive decline of the present invention preferably contains a peptide or a salt thereof consisting of the amino acid sequence set forth in SEQ ID NO: 6. A composition containing the peptide or a salt thereof can suppress the production and / or accumulation of amyloid β by activating neprilysin.

[0037] In one aspect, the composition for improving cognitive function of the present invention preferably contains a peptide or a salt thereof consisting of the amino acid sequence shown in SEQ ID NO: 16. A composition containing the peptide or a salt thereof can inhibit the accumulation of amyloid β by promoting the phagocytic activity of microglial cells.

[0038] The composition for suppressing or ameliorating cognitive decline of the present invention can be used to prevent or ameliorate diseases or conditions associated with cognitive decline. The composition for suppressing or ameliorating cognitive decline can be used, for example, to prevent or ameliorate Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, or age-related cognitive impairment. Cognitive decline is known to occur 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 a familiar place, etc.), disorientation (the ability to correctly recognize one's situation, such as place, time, and people's names), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, decreased executive function, impaired executive function (inability to plan and carry out tasks), decreased concentration, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, and decreased information processing speed. The composition for suppressing or improving cognitive decline of the present invention can be used, for example, to prevent or improve the symptoms of cognitive decline described above. In one aspect, the composition of the present invention can be used to suppress cognitive decline caused by Alzheimer's disease, mild cognitive impairment, or age-related cognitive impairment. In the present invention, suppressing cognitive decline includes suppressing further decline (worsening) of cognitive symptoms, i.e., maintaining cognitive function and delaying decline (worsening) of cognitive function. Improving cognitive function includes 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. Cognitive impairment refers to the inability to perform some or all of the above cognitive functions.

[0039] The content of the peptide or salt thereof comprising any of the amino acid sequences of SEQ ID NOS: 1 to 19, VV, and AY contained in the composition for suppressing or improving cognitive decline is not particularly limited and can be set depending on the form, etc. In one embodiment, the total content of the peptide or salt thereof in the composition for suppressing or improving cognitive decline may be, for example, 0.001% by weight or more, preferably 0.01% by weight or more, and may be 50% by weight or less, preferably 10% by weight or less. In one embodiment, the total content of the peptide or salt thereof in the composition for suppressing or improving cognitive decline may be, for example, 0.001 to 50% by weight, preferably 0.01 to 10% by weight. In one embodiment, when the composition for suppressing or improving cognitive decline is a liquid composition such as a beverage, the total content of the peptide or salt thereof in the composition is preferably 0.01 to 200 mg / mL, more preferably 0.1 to 100 mg / mL.

[0040] The composition for inhibiting or improving cognitive decline of the present invention is preferably taken orally (administered orally). The dosage (which can also be referred to as intake amount) of the composition for inhibiting or improving cognitive decline is not particularly limited. The dosage may be an amount that is sufficient to achieve the effect of inhibiting or improving cognitive decline, and may be appropriately set depending on the dosage form, administration method, subject's body weight, etc. The dosage of the composition for inhibiting or improving cognitive decline is preferably an amount that achieves at least one effect selected from the group consisting of a β-secretase inhibitory effect, a microglial phagocytosis promoting effect, and a neprilysin activation effect.

[0041] In one embodiment, when a composition for suppressing or improving cognitive decline is ingested or administered to a human (adult), the total dose of the peptide or salt thereof is preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and preferably 5,000 mg or less, more preferably 3,000 mg or less, and even more preferably 2,000 mg or less, in peptide equivalent per day. In one embodiment, when a composition for suppressing or improving cognitive decline is ingested or administered to a human (adult), the total dose of the peptide or salt thereof 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, in peptide equivalent per day. When the composition contains two or more of the peptides or salts thereof, the total dose is the combined dose of the peptides or salts thereof. The "peptide-equivalent amount" refers to the amount of the peptide, and when the peptide is in the form of a salt, it refers to the value obtained by multiplying the number of moles of the salt by the molecular weight of the peptide. In one aspect, for example, the dosage of a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a salt thereof may be 0.001 to 5000 mg, preferably 0.01 to 3000 mg, per day in peptide equivalent. The dosage of a peptide consisting of the amino acid sequence of SEQ ID NO: 2 to 19, VV, or AY, or the corresponding salt thereof, may also be 0.001 to 5000 mg, preferably 0.01 to 3000 mg, per day in peptide equivalent. It is preferable to ingest or administer the above amount once or more times per day, for example, once a day or in divided doses (e.g., 2 to 3 times a day). In one aspect, it is preferable to orally ingest or administer the above amount of peptide or salt thereof. In the case of a human (adult), it is preferable to ingest or administer the above amount of peptide or salt thereof per 60 kg of body weight per day. In one aspect, the composition for suppressing or ameliorating cognitive decline may be an oral composition for ingesting or administering the above amount of peptide or salt thereof per 60 kg of body weight per day to a human.

[0042] Hereinafter, the composition containing the peptide of the present invention or a salt thereof and the composition for suppressing or improving cognitive decline will be collectively referred to as the composition of the present invention.

[0043] In one aspect, the composition etc. of the present invention may comprise a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 or a salt thereof, and preferably the composition etc. further comprises a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 2 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences of SEQ ID NOs: 2 to 19, VV, and AY, or a salt thereof, may be one type or two or more types. In one aspect, the composition etc. of the present invention may comprise a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or 2 or a salt thereof, and preferably the composition etc. further comprises a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 3 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences of SEQ ID NOs: 3 to 19, VV, and AY, or a salt thereof, may be one type or two or more types.

[0044] In one aspect, the composition of the present invention may comprise a peptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or a salt thereof, and preferably the composition further comprises a peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 2, 4 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 2, 4 to 19, VV, and AY, or a salt thereof, may be one type or two or more types. In one aspect, the composition of the present invention may comprise a peptide consisting of the amino acid sequence shown in SEQ ID NO: 3 or 4 or a salt thereof, and preferably the composition further comprises a peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 2, 5 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 2, 5 to 19, VV, and AY, or a salt thereof, may be one type or two or more types.

[0045] In one aspect, the composition of the present invention may comprise a peptide consisting of the amino acid sequence shown in SEQ ID NO: 5 or a salt thereof, and preferably the composition further comprises a peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 4, 6 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 4, 6 to 19, VV, and AY, or a salt thereof, may be one type or two or more types. In one aspect, the composition of the present invention may comprise a peptide consisting of the amino acid sequence shown in SEQ ID NO: 5 or 6 or a salt thereof, and preferably the composition further comprises a peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 4, 7 to 19, VV, and AY, or a salt thereof. The peptide consisting of any of the amino acid sequences shown in SEQ ID NOs: 1 to 4, 7 to 19, VV, and AY, or a salt thereof, may be one type or two or more types.

[0046] In one aspect, the composition etc. of the present invention preferably comprises at least one selected from the group consisting of a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof, and more preferably comprises a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

[0047] In one aspect, the composition of the present invention may comprise a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 7 or a salt thereof. Preferably, the composition further comprises a peptide consisting of any of the amino acid sequences of SEQ ID NOs: 1 to 6, 8 to 19, VV, and AY or a salt thereof. The peptide consisting of any of the amino acid sequences of SEQ ID NOs: 1 to 6, 8 to 19, VV, and AY or a salt thereof may be one type or two or more types. In one aspect, the composition of the present invention preferably comprises a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and more preferably further comprises a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

[0048] In one aspect, the composition etc. of the present invention preferably comprises a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 7 or a salt thereof, a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 14 or a salt thereof, a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 21 or a salt thereof, a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 22 or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof, and more preferably further comprises a peptide consisting of any of the amino acid sequences set forth in SEQ ID NOs: 1 to 6, 8 to 13, 15 to 19, VV, and AY or a salt thereof. The peptide consisting of any of the amino acid sequences set forth in SEQ ID NOs: 1 to 6, 8 to 13, 15 to 19, VV, and AY or a salt thereof may be one type or two or more types.

[0049] In one aspect, the composition etc. of the present invention is a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 2 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 3 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 4 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 5 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 6 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 7 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 8 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 9 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 10 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 11 Preferably, the composition of the present invention comprises a peptide or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 12 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 13 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 14 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 15 or a salt thereof, and a peptide or a salt thereof, and more preferably comprises a peptide consisting of the amino acid sequence of SEQ ID NO: 17 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 18 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 19 or a salt thereof, a peptide consisting of the amino acid sequence of VV or a salt thereof, and a peptide or a salt thereof, which consists of the amino acid sequence of AY. More preferably, the composition of the present invention further comprises a peptide consisting of the amino acid sequence of SEQ ID NO: 21 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 22 or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

[0050] The 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 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, a composition for inhibiting or ameliorating cognitive decline can also be referred to as an agent for inhibiting or ameliorating cognitive decline. A composition for inhibiting β-secretase can also be referred to as a β-secretase inhibitor. A composition for promoting phagocytosis in microglial cells can also be referred to as a promoter of phagocytosis in microglial cells. A composition for inhibiting the production and / or accumulation of amyloid β can also be referred to as an inhibitor of amyloid β production and / or accumulation. A composition for activating neprilysin can also be referred to as a neprilysin activator.

[0051] The composition of the present invention may be for oral or parenteral use. Preferably, the composition of the present invention is an oral composition. The composition of the present invention may be in the form of, for example, a food or drink, a pharmaceutical product, a quasi-drug, or a feed, with a food or drink or a pharmaceutical product being preferred, and a food or drink or an oral pharmaceutical product being more preferred. The composition of the present invention can also be added to a food or drink, a pharmaceutical product, a quasi-drug, a feed, or the like. The form of the composition of the present invention is not particularly limited, and may be any of a solid (e.g., powder, granules, tablet, etc.), a liquid, a paste, etc.

[0052] The compositions of the present invention contain the above-mentioned peptides or salts thereof, and 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.

[0053] For example, when the composition of the present invention is made into a food or drink, the above-mentioned peptide or a salt thereof can be blended with ingredients that can be used in foods and drinks (e.g., food ingredients, food additives used as needed, etc.) to produce various foods and drinks. The foods and drinks are not particularly limited, and examples include general foods and drinks, health foods, functional foods, foods for specified health uses, health supplements, foods for patients, etc. The above-mentioned health foods, functional foods, foods for specified health uses, health supplements, etc. can be used in various formulation forms, such as liquids, fine granules, tablets, granules, powders, capsules, chewable tablets, dry syrups, and liquid diets.

[0054] When the composition of the present invention is used as a pharmaceutical or quasi-drug, the peptide or salt thereof can be formulated with a pharmacologically acceptable carrier and, if necessary, additives to produce a pharmaceutical or quasi-drug 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. Pharmaceuticals or quasi-drugs can be administered (ingested) orally or parenterally (transdermally, transmucosally, enterally, by injection, etc.). When the composition of the present invention is used as a pharmaceutical or quasi-drug, it is preferably administered as an oral pharmaceutical or oral quasi-drug. Examples of dosage forms for oral administration include 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.

[0055] When the composition of the present invention is used as feed, the peptide or a salt thereof 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.

[0056] When the composition of the present invention is used, for example, as a food or drink, a pharmaceutical product, a quasi-drug, or a feed, the method for producing it is not particularly limited, and it can be produced by a general method using the above-mentioned peptide or a salt thereof.

[0057] In one embodiment, the composition etc. 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. 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 is obtained by filling and sealing such a container with the beverage.

[0058] In one aspect, the content of the peptide consisting of the amino acid sequence of SEQ ID NO: 1 to 19, VV, or AY, or the corresponding salt thereof, in the composition etc. of the present invention may be 0.0001 to 20 wt %, preferably 0.001 to 10 wt %.

[0059] When the composition of the present invention contains a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof, the total content of the peptides or salts thereof in the composition may be, for example, 0.0001 to 20% by weight, preferably 0.001 to 10% by weight. In one aspect, when the composition of the present invention contains a peptide consisting of the amino acid sequence of SEQ ID NO: 21 or a salt thereof, the content may be, for example, 0.0001 to 20% by weight, preferably 0.001 to 10% by weight. When the composition of the present invention contains a peptide consisting of the amino acid sequence of SEQ ID NO: 22 or a salt thereof, the content may be, for example, 0.0001 to 20% by weight, preferably 0.001 to 10% by weight. When the composition of the present invention contains Cyclo(Trp-Pro) or a salt thereof, the content thereof may be, for example, 0.0001 to 20% by weight, and preferably 0.001 to 10% by weight. In one aspect, when the composition of the present invention is a liquid composition such as a beverage, and contains a peptide consisting of the amino acid sequence of SEQ ID NO: 21 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 22 or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof, the total content of the peptides or salts thereof is preferably 0.00005 to 20 mg / mL, and more preferably 0.0001 to 10 mg / mL. When the composition etc. of the present invention contains a peptide consisting of the amino acid sequence of SEQ ID NO: 21 or a salt thereof, a peptide consisting of the amino acid sequence of SEQ ID NO: 22 or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof, the total dose of these peptides or salts thereof is preferably 0.0001 to 500 mg, more preferably 0.001 to 300 mg, per day in peptide equivalent for a human (adult).

[0060] The composition of the present invention is preferably one that is continuously ingested or administered. By continuously ingesting or administering the peptide or a salt thereof, it is expected that a greater effect can be obtained. In one aspect, the composition of the present invention is 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 peptide or a salt thereof can be ingested as a food or drink, and from the viewpoint of safety, it is thought that there will be few problems with long-term ingestion, for example.

[0061] The subject (which can also be referred to as the administration subject) to which the composition etc. of the present invention is ingested or administered is not particularly limited. It is preferably a human or a non-human mammal, more preferably a human. In one aspect, the administration subject of the present invention includes a subject who needs or desires to inhibit or improve cognitive decline. Further, the administration subject of the present invention includes a subject who needs or desires to prevent or improve a disease or condition associated with cognitive decline, a subject who needs or desires to inhibit the production and / or accumulation of amyloid beta, a subject who needs or desires to prevent or improve a condition or disease associated with amyloid beta accumulation, etc. In one aspect, the administration subject of the present invention includes middle-aged or elderly people. Middle-aged or elderly people include elderly people. Middle-aged or elderly people may be, for example, people aged 40 or older. In one aspect, among middle-aged or elderly people, elderly people are preferred as the subject. Elderly people may be, for example, people aged 60 or older or 65 or older. In one aspect, the administration subject of the composition etc. of the present invention may be a healthy individual. For example, it can also be used in healthy individuals for the purposes of inhibiting or improving cognitive decline, inhibiting the production and / or accumulation of amyloid beta in the brain, preventing the accumulation of amyloid beta in the brain, and preventing cognitive impairment associated with Alzheimer's disease, mild cognitive impairment, or aging.

[0062] The composition of the present invention may be labeled with a function exhibited by inhibiting or improving cognitive decline, or by inhibiting the production and / or accumulation of amyloid beta. Such a label is also referred to as a functional label. The label 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 ability," and labels or functional labels equivalent thereto. In one aspect of the present invention, the composition of the present invention is preferably a food or beverage labeled with one or more of the above labels. The label may also be a label indicating that the composition is used to obtain the above-mentioned function. The label may be attached to the composition itself, or to the container or packaging of the composition.

[0063] The present invention also encompasses the following methods and uses: A method for suppressing or improving a decline in cognitive function by administering a peptide or a salt thereof, wherein the peptide is a peptide consisting of any one of the amino acid sequences selected from the group consisting of GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), LYEGY (SEQ ID NO: 7), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), IGME (SEQ ID NO: 16), VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY. A method for inhibiting the production and / or accumulation of amyloid β, which comprises administering the above peptide or a salt thereof. 1. Use of a peptide or a salt thereof for inhibiting or improving a decline in cognitive function, wherein the peptide is a peptide consisting of any amino acid sequence selected from the group consisting of GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), LYEGY (SEQ ID NO: 7), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15), IGME (SEQ ID NO: 16), VIQY (SEQ ID NO: 17), IWHHT (SEQ ID NO: 18), IVGRPR (SEQ ID NO: 19), VV, and AY. Use of the peptide or a salt thereof for inhibiting the production and / or accumulation of amyloid β. In the above method and use, the peptide or a salt thereof may be used alone or in combination with two or more thereof.In one aspect, in the above-mentioned method and use, it is preferable to use a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and it is even more preferable to use a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

[0064] A method for inhibiting β-secretase, comprising administering a peptide consisting of any one of the amino acid sequences of SEQ ID NOs: 1 to 5, 7 to 15, 17 to 19, VV and AY, or a salt thereof. Use of a peptide consisting of any one of the amino acid sequences of SEQ ID NOs: 1 to 5, 7 to 15, 17 to 19, VV and AY, or a salt thereof, for inhibiting β-secretase.

[0065] A method for activating neprilysin, comprising administering a peptide consisting of the amino acid sequence of GVTHNVPIYEGY (SEQ ID NO: 6) or a salt thereof. Use of a peptide consisting of the amino acid sequence of GVTHNVPIYEGY (SEQ ID NO: 6) or a salt thereof for activating neprilysin.

[0066] A method for promoting phagocytosis of microglial cells, comprising administering a peptide consisting of the amino acid sequence of IGME (SEQ ID NO: 16) or a salt thereof. Use of a peptide consisting of the amino acid sequence of IGME (SEQ ID NO: 16) or a salt thereof for promoting phagocytosis of microglial cells.

[0067] The method may be a therapeutic method or a non-therapeutic method. The use may be a therapeutic use or a non-therapeutic use.

[0068] In the above-mentioned methods and uses, it is preferable to have the subject ingest or administer the peptide or a salt thereof once or more times 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, the peptide or a salt thereof can be used to prevent or ameliorate a disease or condition associated with a decline in cognitive function. In one aspect, the peptide or a salt thereof can be used to prevent or ameliorate a condition or disease associated with amyloid-β accumulation. The present invention also encompasses a method for preventing or ameliorating a condition or disease associated with amyloid-β accumulation, which comprises administering the peptide or a salt thereof.

[0069] In the above-described methods and uses, the peptide or a salt thereof may be used in an amount (which may also be referred to as an effective amount) that achieves the desired effect. The effective amount is preferably an amount that achieves the effect of inhibiting or improving cognitive decline, inhibiting β-secretase, activating neprilysin, or promoting the phagocytosis of microglial cells. The preferred dosage, administration method, and administration target of the peptide or a salt thereof are the same as those of the composition of the present invention described above. The peptide or a salt thereof may be ingested or administered as is, or as a composition containing the peptide or a salt thereof. For example, the composition of the present invention or a composition for inhibiting or improving cognitive decline may be ingested or administered.

[0070] The peptide or a salt thereof can be used for producing foods and beverages, pharmaceuticals, quasi-drugs, feed, etc. that are used to suppress or improve cognitive decline. In one aspect, the present invention also encompasses use of the peptide or a salt thereof in the production of a composition for suppressing or improving cognitive decline. The peptide or a salt thereof can be used for the production of a composition for preventing or improving a condition or disease associated with amyloid beta accumulation (preferably a condition or disease associated with amyloid beta accumulation in the brain).

[0071] 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.

[0072] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0073] <Peptides> Peptides P1 to P21 were used in Examples 1 and 2. Table 1 shows the amino acid sequences of peptides P1 to P21. Peptides P1 to P21 are linear peptides. Peptides P1 to P21 were synthesized by GenScript Biotech. The amino acid sequences of the peptides are shown in single-letter code. pE represents a pyroglutamic acid residue. All amino acids constituting the peptides are in the L-form.

[0074]

[0075] Example 1 Materials and Methods A. Reagents BACE1 Inhibitor Screening Kit (Fluorometric) was obtained from Abeam Inc. Other reagents were purchased from Sigma-Aldrich.

[0076] B. BACE1 Inhibition Assay Peptides P1 to P5, P7 to P15, and P17 to P21 shown in Table 1 were used as candidate compounds. The BACE1 inhibitory activity of the candidate compounds was evaluated using a BACE1 Inhibitor Screening Kit (Fluorometric).

[0077] The BACE1 inhibition assay was performed according to the kit manufacturer's protocol. Candidate compounds were 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 diluted solutions of candidate compounds were used in the following experiments. BACE1 enzyme assay mixtures 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 the candidate compound dilution and transferred to wells of a flat-bottom 96-well black plate to prepare reaction mixtures. Fluorescence (λEx / λEm = 345 / 500 nm) readings from the assay plate were monitored for 30 minutes at 37°C using a Tecan Spark® multimode microplate reader. The relative inhibition rate (%) of each sample was calculated from the fluorescence measurements according to the manufacturer's protocol.

[0078] Statistical analysis was performed using GraphPad Prism version 7.0 (San Diego, California, USA). The best-fit IC value (hereinafter referred to as IC) of each peptide was calculated by applying the concentration and relative inhibition rate to the equation log(peptide) vs. normalized inhibition rate.

[0079] (Results) Each of the peptides P1 to P5, P7 to P15, and P17 to P21 had the effect of inhibiting BACE 1. The IC50 (μg / mL) of peptides P1 to P5, P7 to P15, and P17 to P21 is shown in Table 2.

[0080]

[0081] Tables 3-5 show the relative % inhibition of each peptide tested at various concentrations. Tables 3-5 show the mean % BACE1 inhibition values ​​(N=2). The concentration and % relative inhibition values ​​of each peptide were fitted to the log(peptide) vs. normalized inhibition equation to determine experimental IC50 values ​​(Table 2).

[0082]

[0083]

[0084]

[0085] BACE1 is an aspartyl protease that plays a key role in generating amyloid beta (Aβ) peptides from amyloid precursor proteins. There is a strong positive correlation between Aβ peptide concentrations and cognitive function (Non-Patent Document 1). This, coupled with evidence of elevated BACE1 activity in Alzheimer's disease models (Reference 1), suggests that BACE1 inhibition is a promising strategy for slowing cognitive decline (Reference 2). Results of BACE1 inhibition assays showed that peptides P1-P5, P7-P15, and P17-P21 could inhibit BACE1 with IC50 values ​​ranging from 39.3 to 826.5 μg / mL (Table 2). Reference 1: Fukumoto et al., Arch. Neurol. 2002, 59(9), 1381-1389. Reference 2: McDade et al., J. Neurol. 2002, 59(9), 1381-1389. , Nature Reviews Neurology 2021, 17(11), 703-714.

[0086] Example 2 Materials and Methods A. Reagents Gibco Dulbecco's Modified Eagle's Medium / Nutrient Mixture F-12 Ham 1:1 (DMEM / F12), fetal bovine serum (FBS), horse serum (HS), penicillin / streptomycin (P / S), poly-D-lysine (PDL)-coated 24-well plate, Hanks' Balanced Salt Solution (HBSS), Dulbecco's phosphate-buffered saline (DPBS), sodium pyruvate, D-glucose, BlockAid ＴＭ Blocking Solution, IBA1 polyclonal antibody (IBA1), and Hoechst 33342, Trihydrochloride, and Trihydrate were obtained from Thermo Fisher Scientific. Amyloid β (1-42), HiLyte ＴＭ Fluor 488 (Aβ １－４２ ) and 1% NH ４OH solution was purchased from Anaspec. Triton® X-100 and paraformaldehyde (PFA) were obtained from Sigma-Aldrich.

[0087] B. Aβ １－４２ Preparation of Aβ １－４２ Peptide (Aβ １－４２ Soluble species of Aβ (monomer) were prepared. １－４２ Peptides were diluted with 1% NH ４ The peptide was dissolved in HCl at a concentration of 2 mg / mL in HCl (OH). The peptide solution was further diluted with DPBS to a final concentration of 1 mg / mL stock solution. The reconstituted peptide was aliquoted into several freezer vials and stored at -20°C.

[0088] C. Cell Culture SIM-A9 mouse microglial cells (ATCC CRL-3265) were cultured in DMEM / F12 supplemented with 10% FBS, 5% HS, and 1% P / S under 5% CO ２ The cells were cultured at 37°C in a humidified gas chamber containing

[0089] D. Phagocytosis Assay The peptide P16 (IGME, SEQ ID NO: 16) shown in Table 1 was used as a test compound. SIM-A9 cells (2 × 10 ５ Cells (1000 cells / well) were seeded onto PDL-coated 24-well plates in DMEM / F12 medium and pretreated with 8.8 μg / mL of peptide P16 for 24 hours. After pretreatment, the cells were washed with DMEM / F12 and treated with 4.51 μg / mL of Aβ １－４２ and incubated for an additional 6 hours. At the end of the incubation period, Aβ １－４２ The containing medium was removed and the cells were washed with DPBS to remove extracellular Aβ １－４２ Next, the cells were fixed with 4% PFA, permeabilized with 0.2% Triton® X-100, and then stained with BlockAid ＴＭ The cells were blocked with Blocking Solution at room temperature for 1 hour. Cell shape was visualized using IBA1 antibody, and nuclei were stained with Hoechst 33342. Five sets of images were acquired per well for analysis, and intracellular Aβ was detected. １－４２ Cells containing Aβ１－４２ Phagocytic activity was determined by colocalization of Aβ / IBA1 / nuclear signals. １－４２ The values ​​were expressed as the average number of microglial cells normalized to the control group (cells not treated with peptide P16).

[0090] E. Neprilysin (NEP) Activity Assay Peptide P6 (GVTHNVPIYEGY, SEQ ID NO: 6) shown in Table 1 was used as a test compound. qf-Aβ(12-16)AAC (a peptide with the sequence VHHQKAAC (SEQ ID NO: 20) having methylcoumarinamide (MCA) attached to the Cys side chain and 2,4-dinitrophenol (DNP) as a quencher attached to the N-terminus of the peptide) was synthesized. The synthesized qf-Aβ(12-16)AAC was dissolved in DMSO to form a 2 mM stock solution. SIM-A9 cells (4 × 10 ４ Cells (12-16 cells / well) were seeded in DMEM / F12 medium onto PDL-coated 96-well plates as described above and pretreated with 2.2 μg / mL of peptide P6 for 24 hours. The medium was then replaced with 200 μL of assay buffer (DPBS containing 5.5 mM D-glucose, 0.3 mM sodium pyruvate, 25 mM sodium bicarbonate, and 1.5 μM zinc sulfate) containing 4 μM qf-Aβ(12-16)AAC, and the cells were incubated for 1 hour. To measure NEP activity, 150 μL of the assay buffer was aliquoted and measured for fluorescence at an excitation wavelength of 328 nm and an emission wavelength of 393 nm using a TECAN Spark® (TECAN, USA).

[0091] F. Statistical Analysis Statistical analysis was performed using GraphPad Prism version 7.0 (San Diego, California, USA). All results are presented as mean ± standard deviation (SD). Statistical analysis was performed by Student's t-test. Data were considered significant when the P value was p<0.05.

[0092] (Results) A. Aβ in SIM-A9 cells １－４２Effect of peptides on phagocytosis of Aβ Microglia are immune cells resident in the brain, performing various functions such as monitoring the brain microenvironment and removing cellular debris. Microglial cells are known to phagocytose various forms of Aβ, and enhancing this clearance mechanism is expected to be a therapeutic strategy for Alzheimer's disease (AD). Figure 1 shows the results of evaluating the phagocytic activity of microglia (SIM-A9 cells) treated with peptide P16. The vertical axis represents the amount of Aβ present within the cells. １－４２ The figures show the relative values ​​of the number of microglial cells containing Aβ. The results are shown relative to the control. The values ​​represent the mean ± SD (n = 3). * indicates a significant difference from the control at p < 0.05. Pretreatment with peptide P16 reduced Aβ １－４２ It was found that the phagocytic activity of SIM-A9 cells incubated with the monomer could be significantly promoted (Fig. 1).

[0093] B. Effect of peptides on NEP enzyme activity Aβ is also degraded by endopeptidases such as NEP. Increasing the activity of Aβ-degrading enzymes is one of the clearance mechanisms being investigated for the treatment of AD. Figure 2 is a graph showing the results of evaluating NEP enzyme activity in microglia treated with peptide P6. Values ​​represent the mean ± SD (n = 3). Results are shown relative to the control. ** indicates a significant difference of p < 0.01 compared to the control. Treatment with peptide P6 significantly increased NEP enzyme activity (Figure 2).

[0094] Example 3 Materials and Methods A. Reagents and Peptides Gibco Opti-MEM ＴＭReduced serum medium (Opti-MEM), fetal calf serum (FCS), penicillin / streptomycin (P / S), hygromycin B, and blasticidin S hydrochloride were obtained from Thermo Fisher Scientific. MSD® 96-well MULTISPOT® 6E10 Abeta Triplex Assay kit (amyloid-β detection kit) was purchased from Meso Scale Discovery. N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT, γ-secretase inhibitor) was obtained from Calbiochem.

[0095] The test peptides used in Example 3 are shown below. All test peptides were synthesized by GenScript Biotech. LYEGY: Peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) ILPVPA: Peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) FLPM: Peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) FQPSF: Peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) Cyclo (Trp-Pro): Cyclic dipeptide having a structure in which tryptophan and proline are condensed and bonded. The above peptides LYEGY, ILPVPA, FLPM, and FQPSF are linear peptides.

[0096] B. Cell Culture and Treatment. The human H4 glioma cell line was stably transfected with the pAG3 vector containing human amyloid precursor protein isoform 695 (APP695) with the Swedish double mutation K595N / M596L to generate H4-hAPP cells. The pAG3 vector is a modified pcDNA3 plasmid containing a hygromycin B resistance cassette with a transgene under the control of a fused CMV and chicken β-actin promoter. H4-hAPP cells were cultured in Opti-MEM (cell culture medium) supplemented with 10% FCS, 1% P / S, 200 μg / mL hygromycin B, and 2.5 μg / mL blasticidin S hydrochloride in a humidified incubator. Cells were seeded into 96-well plates at a density of 25,000 cells / well and incubated at 5% CO. ２ The test peptides were reconstituted in the cell culture medium to prepare a peptide mixture containing five peptides. The concentrations of the peptides in the peptide mixture are shown in Table 6.

[0097]

[0098] H4-hAPP cells were treated with the peptide mixture or cell culture medium supplemented with DAPT (DAPT concentration: 400 nM) as a positive control. H4-hAPP cells without peptide mixture treatment or DAPT treatment served as controls. After 24 hours of treatment at 37°C, cell culture supernatants were collected for amyloid-β (Aβ) analysis. Two independent experiments were performed.

[0099] C. Amyloid-β ELISA Assay Cell culture supernatants were diluted 1:10 and assayed for human amyloid-β using the 6E10 Abeta Triple Assay kit. １－３８ (Aβ38), and human amyloid beta １－４２ (Aβ42) was analyzed. The multiplex assay was performed according to the manufacturer's instructions, and plates were read on a Sector Imager 2400 (Meso Scale Discovery). Aβ concentrations were calculated by reference to a standard curve. The sensitivity of the multiplex kit was <5 pg / mL.

[0100] D. Statistical Analysis Statistical analysis was performed using GraphPad Prism version 5.0 (San Diego, California, USA). All results were expressed as mean ± standard deviation (SD). Statistical analysis was performed by analysis of variance (ANOVA) followed by a posthoc Dunnett's multiple comparison test. Data were considered significant when p-value was p<0.05.

[0101] (Results) The results are shown in Figures 3A and 3B (**: p<0.01, ***: p<0.001, vs. control). Figure 3A shows the amyloid β in the culture supernatant of H4-hAPP cells treated with the peptide mixture. １－３８ 3B is a graph showing the concentration of amyloid β (Aβ38) in the culture supernatant of H4-hAPP cells treated with the peptide mixture. １－４２ The results are shown as mean ± SD (N=2). The peptide mixture inhibited the amyloid β (Aβ42) concentration in H4-hAPP cells. １－３８ and amyloid beta １－４２ suppressed the production of

Claims

1. A composition comprising a peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15) and IGME (SEQ ID NO: 16), or a salt thereof.

2. The composition according to claim 1, which is used for preventing or improving cognitive function decline.

3. The composition according to claim 1 or 2, comprising a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and further comprising a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

4. The composition according to claim 1 or 2, further comprising a peptide or a salt thereof consisting of any one of the amino acid sequences selected from the group consisting of VIQY (sequence number 17), IWHHT (sequence number 18), IVGRPR (sequence number 19), VV and AY.

5. A composition for inhibiting or improving decline in cognitive function, comprising a peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (sequence number 7), GGRYY (sequence number 1), AHDGGRYY (sequence number 2), AEYY (sequence number 3), AEYYRA (sequence number 4), GVTHNVP (sequence number 5), GVTHNVPIYEGY (sequence number 6), ISGW (sequence number 8), IKGY (sequence number 9), pEAPH (sequence number 10), LTEAP (sequence number 11), DLTVTN (sequence number 12), pEIISAN (sequence number 13), ILPVPA (sequence number 14), TERGYS (sequence number 15), IGME (sequence number 16), VIQY (sequence number 17), IWHHT (sequence number 18), IVGRPR (sequence number 19), VV and AY, or a salt thereof.

6. The composition described in claim 5, which inhibits the production and / or accumulation of amyloid beta.

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

8. The composition according to claim 5 or 6, comprising a peptide consisting of the amino acid sequence of LYEGY (SEQ ID NO: 7) or a salt thereof, and a peptide consisting of the amino acid sequence of ILPVPA (SEQ ID NO: 14) or a salt thereof, and further comprising a peptide consisting of the amino acid sequence of FLPM (SEQ ID NO: 21) or a salt thereof, a peptide consisting of the amino acid sequence of FQPSF (SEQ ID NO: 22) or a salt thereof, and Cyclo(Trp-Pro) or a salt thereof.

9. The composition according to claim 5 or 6, which comprises a peptide consisting of the amino acid sequence GVTHNVPIYEGY (SEQ ID NO: 6) or a salt thereof, and inhibits accumulation of amyloid β by activating neprilysin.

10. The composition according to claim 5 or 6, which comprises a peptide having the amino acid sequence of IGME (sequence number 16) or a salt thereof, and inhibits accumulation of amyloid beta by promoting the phagocytosis of microglial cells.

11. The composition according to claim 1 or 5, wherein the composition is an oral composition.

12. The composition according to claim 1 or 5, wherein the composition is a food or beverage product or an oral medicine.

13. The composition according to claim 1 or 5, wherein the composition is labeled with at least one function 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", "enhancing short-term and long-term memory", "promoting verbal and visuospatial memory" and "maintaining or improving logical thinking ability".

14. A peptide consisting of any amino acid sequence selected from the group consisting of LYEGY (SEQ ID NO: 7), GGRYY (SEQ ID NO: 1), AHDGGRYY (SEQ ID NO: 2), AEYY (SEQ ID NO: 3), AEYYRA (SEQ ID NO: 4), GVTHNVP (SEQ ID NO: 5), GVTHNVPIYEGY (SEQ ID NO: 6), ISGW (SEQ ID NO: 8), IKGY (SEQ ID NO: 9), pEAPH (SEQ ID NO: 10), LTEAP (SEQ ID NO: 11), DLTVTN (SEQ ID NO: 12), pEIISAN (SEQ ID NO: 13), ILPVPA (SEQ ID NO: 14), TERGYS (SEQ ID NO: 15) and IGME (SEQ ID NO: 16), or a salt thereof.