WO2023120407A1 - アミロイドβの産生抑制及び／又は蓄積抑制用組成物 - Google Patents

アミロイドβの産生抑制及び／又は蓄積抑制用組成物 Download PDF

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WO2023120407A1
WO2023120407A1 PCT/JP2022/046366 JP2022046366W WO2023120407A1 WO 2023120407 A1 WO2023120407 A1 WO 2023120407A1 JP 2022046366 W JP2022046366 W JP 2022046366W WO 2023120407 A1 WO2023120407 A1 WO 2023120407A1
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phe
amyloid
composition
cyclo
accumulation
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PCT/JP2022/046366
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English (en)
French (fr)
Japanese (ja)
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嘉宏 中尾
シャンメイ ヨン
シャージャン リン
グレース カー ヤン チャン
翔太 野中
義 古元
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サントリーホールディングス株式会社
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for suppressing production and/or accumulation of amyloid ⁇ , and the like.
  • Amyloid ⁇ (A ⁇ ) is a type of protein produced in the brain. When amyloid ⁇ aggregates to oligomerize or fibrillate, it exhibits neuronal toxicity. In addition, aggregated amyloid ⁇ accumulates without being discharged from the brain, and is thought to trigger the onset of Alzheimer's disease. Therefore, suppressing the production or accumulation of amyloid ⁇ is considered effective, for example, in preventing Alzheimer's disease or in suppressing progression of the disease.
  • Acetylcholinesterase inhibitors are known as drugs that improve symptoms of Alzheimer's disease. Inhibition of acetylcholinesterase increases the amount of acetylcholine in the brain and is effective in suppressing the progression of cognitive decline. However, acetylcholinesterase inhibition cannot suppress the production of amyloid ⁇ or remove accumulated amyloid ⁇ . There is a demand for a substance that can be ingested on a daily basis as food or drink, etc., and that can suppress the production or accumulation of amyloid ⁇ .
  • Patent Document 1 describes an agent for suppressing and/or improving cognitive function decline containing Cyclo (Gly-Pro).
  • An object of the present invention is to provide a composition for suppressing the production and/or accumulation of amyloid ⁇ .
  • the present inventors have conducted intensive studies in view of the above problems, and have found that a cyclic dipeptide, cyclophenylalanylphenylalanine (Cyclo(Phe-Phe)), is effective in suppressing the production and/or accumulation of amyloid ⁇ . Found it.
  • the present invention relates to, but is not limited to, the following compositions for suppressing production and/or accumulation of amyloid ⁇ .
  • a composition for suppressing production and/or accumulation of amyloid ⁇ comprising Cyclo(Phe-Phe) or a salt thereof as an active ingredient.
  • the composition of [1] above which suppresses the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • composition according to any one of [1] to [4] above, which is a food or drink or a pharmaceutical.
  • the composition "enhances cognitive function”, “suppresses deterioration of cognitive function”, “maintains good cognitive function”, “improves memory”, “suppresses deterioration of memory”, “improves memory “maintaining good memory”, “improving memory accuracy”, “preventing memory impairment”, “improving memory impairment”, “maintaining memory as a part of cognitive function”, and “preventing memory loss” functions that are suitable for people to become,””improve memory accuracy and judgment accuracy, which are part of cognitive function", “improve memory retention or consolidation”, “maintain enhanced cognitive function", “improves executive function”, “promotes attention and concentration”, “improves learning ability”, “maintains and improves orientation", “delays age-related cognitive decline", Labeling of one or more functions selected from the group consisting of "strengthening short-term and long-term memory,””promoting verbal and
  • compositions for suppressing the production and/or accumulation of amyloid ⁇ can be provided.
  • the composition of the present invention can be used as foods, beverages, pharmaceuticals, etc. for suppressing the production and/or accumulation of amyloid ⁇ .
  • FIG. 1 is a graph showing the ⁇ -secretase (BACE) inhibitory activity of Cyclo(Phe-Phe) and Cyclo(Leu-Ala).
  • FIG. 2 shows cells of SIM-A9 microglia (CFF) pretreated with Cyclo(Phe-Phe) for 24 hours and SIM-A9 microglia (vehicle control (VC)) not treated with Cyclo(Phe-Phe).
  • CFF SIM-A9 microglia
  • VC vehicle control
  • FIG. 3 shows the amount of internal amyloid- ⁇ monomer (*: p ⁇ 0.05 vs. vehicle control).
  • FIG. 5 is a graph showing the concentration of amyloid ⁇ 1-38 in the culture supernatant of H4 glioma cells (H4-hAPP cells) overexpressing the amyloid precursor protein wild type with the Swedish double mutation K595N/M596L. (***: p ⁇ 0.001 vs. vehicle control).
  • FIG. 6 is a graph showing the concentration of amyloid ⁇ 1-40 in the culture supernatant of H4-hAPP cells (***: p ⁇ 0.001 vs. vehicle control).
  • FIG. 7 is a graph showing the concentration of A ⁇ 1-42 in the culture supernatant of H4-hAPP cells (***: p ⁇ 0.001 vs. vehicle control).
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention contains Cyclo(Phe-Phe) or a salt thereof.
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention contains Cyclo(Phe-Phe) or a salt thereof as an active ingredient.
  • the composition for suppressing the production and/or accumulation of amyloid ⁇ of the present invention is sometimes referred to as the composition of the present invention.
  • the composition of the present invention is used to suppress the production of amyloid ⁇ and/or the accumulation of amyloid ⁇ .
  • Cyclo(Phe-Phe) (cyclophenylalanylphenylalanine) used in the present invention is a cyclic dipeptide having a structure in which two phenylalanine molecules are condensed.
  • Cyclo(Phe-Phe) is sometimes referred to as CFF.
  • the term "cyclic dipeptide" is characterized by having amino acids as constituent units, and is a diketopiperazine structure produced by dehydration condensation between the amino group of the N-terminal side amino acid and the carboxyl group of the C-terminal side amino acid.
  • the salt of Cyclo(Phe-Phe) is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for food and drink, and may be either an acid salt or a basic salt.
  • Acid salts include, for example, inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates; Examples include organic acid salts such as acid salts and propionate salts.
  • basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
  • Cyclo(Phe-Phe) or a salt thereof are not particularly limited. Cyclo(Phe-Phe) or a salt thereof can be produced according to known methods. Cyclo(Phe-Phe) or a salt thereof may be derived from a natural product, may be artificially synthesized, may be produced by an enzymatic method or a microbial fermentation method, and may be a linear It may be synthesized by dehydrating and cyclizing the dipeptide. For example, protein hydrolysates, such as collagen hydrolysates, can be heated to yield heat-treated peptides rich in cyclic dipeptides, such as Cyclo(Phe-Phe).
  • Cyclo(Phe-Phe) or a salt thereof may be incorporated into the composition using a protein hydrolyzate containing it or a heat-treated product thereof, a concentrate of the protein hydrolyzate or a heat-treated product thereof, a dry powder Or you may mix
  • the composition of the present invention contains, for example, a protein hydrolyzate or heat treated product thereof, and Cyclo(Phe-Phe) or a salt thereof may be part of the protein hydrolyzate or heat treated product thereof. Cyclo(Phe-Phe) or a salt thereof can also be used as a commercially available product.
  • Amyloid- ⁇ is a peptide sometimes referred to as amyloid- ⁇ protein, amyloid- ⁇ peptide or ⁇ -amyloid.
  • Amyloid ⁇ is usually a peptide consisting of around 40 amino acids, and includes amyloid ⁇ 1-42 , amyloid ⁇ 1-40 , amyloid ⁇ 1-38 and the like. Unassociated amyloid- ⁇ is sometimes referred to as amyloid- ⁇ monomer.
  • Two or more amyloid ⁇ s may form an aggregate.
  • Amyloid ⁇ may form, for example, a soluble aggregate (amyloid ⁇ oligomer) in which two or more (eg, 2 to 50) amyloid ⁇ aggregates.
  • Amyloid ⁇ oligomers include amyloid ⁇ 1-42 oligomers, amyloid ⁇ 1-40 oligomers, amyloid ⁇ 1-38 oligomers, and the like.
  • Amyloid ⁇ in the present invention includes non-aggregated amyloid ⁇ and amyloid ⁇ forming aggregates such as oligomers.
  • Amyloid- ⁇ is produced in the form of amyloid- ⁇ monomers by the two-step cleavage of amyloid- ⁇ precursor protein (APP) by ⁇ -secretase and ⁇ -secretase.
  • APP amyloid- ⁇ precursor protein
  • ⁇ -Secretase is the rate-limiting enzyme for amyloid ⁇ production, and its cleavage regulates the total amyloid ⁇ production. Therefore, by inhibiting ⁇ -secretase, the production of amyloid ⁇ can be suppressed, and the accumulation of amyloid ⁇ can be suppressed.
  • Cyclo(Phe-Phe) or a salt thereof has a ⁇ -secretase inhibitory action.
  • the composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • Cyclo(Phe-Phe) or salts thereof are useful as active ingredients for ⁇ -secretase inhibition.
  • Compositions for inhibiting ⁇ -secretase comprising Cyclo(Phe-Phe) or salts thereof are also encompassed by the present invention.
  • Cyclo(Phe-Phe) or its salts promote phagocytosis of microglial cells.
  • Microglial cells are central nervous system cells present in the brain. Microglial cells play an important role in maintaining the environment in the brain, and one of their actions is the phagocytosis of extracellular proteins such as amyloid ⁇ and brain waste products such as damaged cells. . Promoting phagocytosis of microglial cells promotes the removal of amyloid- ⁇ . Therefore, promotion of phagocytosis of microglial cells is effective in suppressing the accumulation of amyloid ⁇ . Cyclo(Phe-Phe) or a salt thereof is useful as an active ingredient for promoting phagocytosis of microglial cells.
  • the composition of the present invention can be used to suppress the accumulation of amyloid ⁇ by promoting phagocytosis (phagocytosis) of microglial cells.
  • phagocytosis phagocytosis
  • a composition for promoting phagocytosis of microglial cells containing Cyclo(Phe-Phe) or a salt thereof is also included in the present invention.
  • the composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ in the brain.
  • the composition of the present invention is used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase and/or promoting phagocytosis of microglial cells. be able to.
  • the composition of the present invention can be used to suppress production and/or accumulation of one or more types of amyloid ⁇ .
  • the composition of the present invention can be used for the prevention or amelioration of a condition or disease associated with amyloid ⁇ accumulation, preferably a condition or disease associated with amyloid ⁇ accumulation in the brain.
  • conditions or diseases include conditions or diseases associated with or caused by amyloid- ⁇ accumulation.
  • Conditions or diseases associated with or resulting from accumulation of amyloid ⁇ in the brain include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
  • the composition of the present invention can be used to prevent or ameliorate the above conditions or diseases, and can be preferably used for the prevention of the above conditions or diseases.
  • prevention of a condition or disease includes preventing onset, delaying onset, reducing the rate of onset, reducing risk of onset, and the like.
  • Ameliorating a condition or disease includes ameliorating the subject from the condition or disease, alleviating symptoms of the condition or disease, ameliorating symptoms of the condition or disease, slowing progression of the condition or disease, preventing the condition or disease. etc.
  • Cognitive function is known to decline in Alzheimer's disease and mild cognitive impairment.
  • Symptoms of cognitive decline in Alzheimer's disease and mild cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficult to name things), apraxia, agnosia (walking in familiar places). (e.g., getting lost), decreased orientation (the ability to correctly recognize one's own situation, such as place, time, name of person, etc.), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, executive function executive dysfunction (inability to plan and do things), decreased ability to concentrate, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, decreased information processing speed, etc.
  • a preventive effect on cognitive function decline or an improving effect on cognitive function for example, an effect on preventing or improving the above symptoms can be obtained.
  • compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use).
  • Non-therapeutic is a concept that does not involve medical intervention, i.e. human surgery, treatment or diagnosis.
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
  • the agent itself can be provided as a composition, or a composition containing the agent can be provided.
  • the composition for suppressing the production and/or accumulation of amyloid ⁇ of the present invention can also be said to be an agent for suppressing the production and/or accumulation of amyloid ⁇ .
  • a ⁇ -secretase inhibitory composition can also be referred to as a ⁇ -secretase inhibitor.
  • the composition for promoting phagocytosis of microglial cells can also be called an agent for promoting phagocytosis of microglial cells.
  • compositions of the invention may be either oral or parenteral.
  • the compositions of the invention are preferably oral compositions.
  • the composition of the present invention can be in the form of, for example, foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. Foods, beverages, or pharmaceuticals are preferred.
  • the composition of the present invention can also be used by adding it to foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like.
  • the form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granule, tablet, etc.), liquid, paste, or the like.
  • composition of the present invention contains Cyclo (Phe-Phe) or a salt thereof, and further contains various diluents, acidulants, antioxidants, stabilizers, preservatives, etc. that are acceptable as additives for food, beverages, pharmaceuticals, etc.
  • Ingredients, flavors, emulsifiers, pigments, seasonings, pH adjusters, nutritional enhancers, and the like may be added.
  • composition of the present invention when used as a food or drink, Cyclo (Phe-Phe) or a salt thereof may be added to components that can be used for food or drink (e.g., food materials, food additives used as necessary, etc.) can be blended to make various food and drink products.
  • Food and drink are not particularly limited, and examples thereof include general food and drink, health food, food with function claims, food for specified health use, health supplement, and food for the sick.
  • Health foods, foods with function claims, foods for specified health uses, health supplements, etc. are various formulations such as liquids, fine granules, tablets, granules, powders, capsules, chewable formulations, dry syrups, and liquid diets. Can be used as a form.
  • composition of the present invention When the composition of the present invention is used as a drug or quasi-drug, Cyclo (Phe-Phe) or a salt thereof is blended with a pharmacologically acceptable carrier, an optional additive, etc. , various dosage forms of pharmaceuticals or quasi-drugs.
  • Such carriers, additives, etc. may be those that can be used for pharmaceuticals or quasi-drugs and are pharmacologically acceptable.
  • antioxidants, coloring agents and the like can be mentioned.
  • administration (ingestion) forms of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, enteral, injection, etc.) forms of administration.
  • composition of the present invention When used as a drug or quasi-drug, it is preferably an oral drug or oral quasi-drug.
  • Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, dragees, capsules, suspensions, emulsions, chewables and the like.
  • Dosage forms for parenteral administration include, for example, injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants) and the like.
  • the pharmaceutical may be a non-human veterinary pharmaceutical.
  • Cyclo (Phe-Phe) or a salt thereof may be added to the feed.
  • Feed also includes feed additives. Examples of feeds include livestock feeds for cows, pigs, chickens, sheep, horses, etc.; small animal feeds for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.;
  • the composition of the present invention when used as a food or drink, a drug, a quasi-drug, a feed, etc., the production method is not particularly limited, and Cyclo (Phe-Phe) or a salt thereof may be used to prepare a general It can be manufactured by a method.
  • the composition of the present invention is preferably a liquid composition, more preferably a beverage.
  • the beverage may be, for example, a functional beverage.
  • the form of the beverage is not particularly limited, and may be a packaged beverage.
  • Containers for packaged beverages are not particularly limited, and containers of any shape and material may be used. For example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; Containers; glass containers such as glass bottles; and wooden containers such as barrels. Any of commonly used containers can be used.
  • a packaged beverage is obtained by filling and sealing such a container with a beverage.
  • the content of Cyclo(Phe-Phe) or a salt thereof contained in the composition of the present invention is not particularly limited, and can be set according to its form and the like.
  • the content of Cyclo(Phe-Phe) or a salt thereof in the composition of the present invention may be, for example, 1 ⁇ 10 ⁇ 6 wt % or more, preferably 1 ⁇ 10 ⁇ 5 wt % or more, Further, it may be 90% by weight or less, 1 ⁇ 10 ⁇ 1 % by weight or less, or 1 ⁇ 10 ⁇ 2 % by weight or less.
  • the content of Cyclo(Phe-Phe) or a salt thereof may be, for example, 1 ⁇ 10 ⁇ 6 to 90% by weight in the composition of the invention.
  • the content of Cyclo(Phe-Phe) or a salt thereof in the composition of the present invention may be from 1 ⁇ 10 ⁇ 6 to 1 ⁇ 10 ⁇ 1 wt %, and from 1 ⁇ 10 ⁇ 6 to 1 ⁇ 10 ⁇ 2 wt % is preferred, and 1 ⁇ 10 ⁇ 5 to 1 ⁇ 10 ⁇ 2 wt % is more preferred.
  • the content of Cyclo(Phe-Phe) or a salt thereof is 1 ⁇ 10 ⁇ 6 to 1 ⁇ 10 ⁇ 1 % by weight is preferred, 1 ⁇ 10 ⁇ 6 to 1 ⁇ 10 ⁇ 2 wt % is more preferred, and 1 ⁇ 10 ⁇ 5 to 1 ⁇ 10 ⁇ 2 wt % is even more preferred.
  • Cyclo(Phe-Phe) or a salt thereof can be quantified by a known method, for example, by liquid chromatography-mass spectrometry (LC/MS).
  • the composition of the present invention is preferably taken orally (orally administered). There is no particular limitation on the dose (which can also be referred to as intake) of the composition of the present invention.
  • the dosage of the composition of the present invention may be an amount that provides an effect of inhibiting the production and/or accumulation of amyloid ⁇ , and may be appropriately set according to the dosage form, administration method, body weight of the subject, and the like. .
  • the dosage of the composition of the present invention is preferably such that the ⁇ -secretase inhibitory effect and/or the microglial phagocytosis promoting effect can be obtained.
  • the dosage when the composition of the present invention is ingested or administered to a human (adult) subject, the dosage is preferably 1 ⁇ g or more per day as a dose of Cyclo(Phe-Phe), and more It is preferably 10 ⁇ g or more, more preferably 150 ⁇ g or more, and preferably 1000 ⁇ g or less, more preferably 500 ⁇ g or less, and still more preferably 300 ⁇ g or less.
  • the dose of Cyclo(Phe-Phe) when the composition of the present invention is ingested or administered to humans (adults), the dose of Cyclo(Phe-Phe) is preferably 1 to 1000 ⁇ g, more preferably 10 to 500 ⁇ g per day, More preferably 150 to 300 ⁇ g.
  • Cyclo(Phe-Phe) or a salt thereof in the above amount is preferably taken or administered orally.
  • the composition of the present invention may be an oral composition for ingesting or administering to humans Cyclo(Phe-Phe) or a salt thereof in the above amount per 60 kg body weight per day.
  • composition of the present invention is preferably taken or administered continuously. Continuous ingestion or administration of Cyclo(Phe-Phe) or a salt thereof is expected to provide greater effects.
  • the composition of the present invention is preferably taken or administered continuously for one week or longer, more preferably for four weeks or longer, and even more preferably for eight weeks or longer. Cyclo(Phe-Phe) or a salt thereof can be ingested as a food or drink, and from the viewpoint of safety, long-term ingestion is considered to cause few problems.
  • Subjects to whom the composition of the present invention is ingested or administered are not particularly limited. Humans or non-human mammals are preferred, and humans are more preferred.
  • the subject to which the composition of the present invention is administered is a subject who needs or desires suppression of amyloid ⁇ production and/or accumulation, and a subject who needs prevention or improvement of a condition or disease associated with amyloid ⁇ accumulation.
  • administration subjects in the present invention include middle-aged and elderly people.
  • Middle-aged and elderly people include elderly people.
  • a middle-aged person may be, for example, a person over the age of 40.
  • elderly people are preferred as subjects.
  • a senior citizen may be, for example, a human over the age of 60 or over the age of 65.
  • the subject of administration of the composition of the present invention may be a healthy subject.
  • it can be used in healthy individuals for the purpose of suppressing the production and/or accumulation of amyloid ⁇ in the brain, preventing the accumulation of amyloid ⁇ in the brain, preventing Alzheimer's disease or mild cognitive impairment, and the like.
  • composition of the present invention may be labeled with a function exerted by suppressing the production and/or accumulation of amyloid ⁇ .
  • indication is also called functionality indication.
  • the display is not particularly limited. Such indications include, for example, “increases cognitive function”, “suppresses deterioration of cognitive function”, “maintains good cognitive function”, “improves memory”, “suppresses deterioration of memory”, and “improves memory”.
  • the composition of the present invention is preferably a food or drink labeled with one or more of the above labels.
  • the above indication may be an indication that the above composition is used to obtain the above functions.
  • the label may be attached to the composition itself, or may be attached to the container or packaging of the composition.
  • the invention also includes the following methods and uses.
  • a method for suppressing production and/or accumulation of amyloid ⁇ comprising administering Cyclo(Phe-Phe) or a salt thereof.
  • a method of inhibiting ⁇ -secretase comprising administering Cyclo(Phe-Phe) or a salt thereof.
  • a method for promoting phagocytosis of microglial cells comprising administering Cyclo(Phe-Phe) or a salt thereof.
  • Use of Cyclo(Phe-Phe) or a salt thereof for suppressing production and/or accumulation of amyloid ⁇ Use of Cyclo(Phe-Phe) or salts thereof to inhibit ⁇ -secretase.
  • Cyclo(Phe-Phe) or salts thereof for promoting phagocytosis of microglial cells.
  • the method may be a therapeutic method or a non-therapeutic method.
  • the use may be therapeutic use or non-therapeutic use.
  • Cyclo(Phe-Phe) or a salt thereof can be used to suppress production and/or accumulation of one or more types of amyloid ⁇ .
  • Cyclo(Phe-Phe) or a salt thereof can be used to suppress the production and/or accumulation of amyloid ⁇ through ⁇ -secretase inhibition. In one aspect, Cyclo(Phe-Phe) or salts thereof can be used to inhibit amyloid- ⁇ accumulation by promoting phagocytosis of microglial cells.
  • Cyclo(Phe-Phe) or a salt thereof may be ingested or administered to the subject once or more times a day, for example, once to several times (for example, 2 to 3 times) a day. preferable.
  • the above uses are preferably in humans or non-human mammals, more preferably in humans.
  • Cyclo(Phe-Phe) or a salt thereof is used to prevent or ameliorate conditions or diseases associated with accumulation of amyloid ⁇ by inhibiting ⁇ -secretase and/or promoting phagocytosis of microglial cells. can be done.
  • the present invention also includes a method for preventing or ameliorating a condition or disease associated with amyloid ⁇ accumulation, comprising administering Cyclo(Phe-Phe) or a salt thereof.
  • Cyclo(Phe-Phe) or a salt thereof may be used in an amount (which can also be referred to as an effective amount) capable of suppressing the production and/or accumulation of amyloid ⁇ .
  • the above-mentioned effective amount is preferably an amount that provides ⁇ -secretase inhibitory effect and/or microglial cell phagocytosis promoting effect.
  • Cyclo(Phe-Phe) or a salt thereof is the same as the composition of the present invention described above with respect to the preferred dose, administration method, administration subject, and the like. Cyclo(Phe-Phe) or a salt thereof may be ingested or administered as is, or may be ingested or administered as a composition containing it. For example, a composition of the invention may be ingested or administered.
  • Cyclo(Phe-Phe) or a salt thereof can be used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. that are used to suppress the production and/or accumulation of amyloid ⁇ .
  • the present invention also includes the use of Cyclo(Phe-Phe) or a salt thereof in the production of a composition for suppressing the production and/or accumulation of amyloid ⁇ .
  • the present invention also includes the use of Cyclo(Phe-Phe) or a salt thereof in the manufacture of a composition for inhibiting ⁇ -secretase or a composition for promoting phagocytosis of microglial cells. Cyclo(Phe-Phe) or a salt thereof can be used for the manufacture of a composition for preventing or improving conditions or diseases associated with amyloid ⁇ accumulation.
  • a range represented by “1-2” means from 1 to 2 and includes 1 and 2.
  • the upper limit and the lower limit may be any combination of ranges.
  • Example 1 ⁇ Examples 1 to 4 and Comparative Example 1> (Screening for compounds having ⁇ -secretase inhibitory activity) The test compounds were examined for ⁇ -secretase inhibitory activity. Cyclophenylalanylphenylalanine (Cyclo(Phe-Phe)) (Examples 1 to 4) and cycloleucylalanine (Cyclo(Leu-Ala)) (Comparative Example 1), which are cyclic dipeptides, were used as test compounds. (both from Bachem). A commercially available kit, Beta Secretase (BACE1) Activity Assay Kit (abcam), was used to evaluate the ⁇ -secretase inhibitory activity.
  • BACE1 Beta Secretase
  • abcam Activity Assay Kit
  • the ⁇ fluorescence intensity of the reaction solution ((fluorescence intensity at the end of the reaction (60 minutes)) ⁇ (fluorescence intensity before the start of the reaction (0 minutes)) was used to evaluate the enzyme activity.
  • a group to which no test compound was added was used as a control.
  • the inhibitor attached to the kit was used as a positive control.
  • the BACE activity shown in FIG. 1 is a relative value of the BACE activity of the test compound ( ⁇ fluorescence intensity of the reaction solution to which the test compound was added) when the BACE activity of the control ( ⁇ fluorescence intensity of the reaction solution of Control) is set to 1. is.
  • a decrease in ⁇ -secretase enzymatic activity was confirmed for Cyclo(Phe-Phe). Cyclo(Phe-Phe), a cyclic dipeptide, was found to have ⁇ -secretase inhibitory activity.
  • ⁇ -Amyloid 1-42
  • HiLyte TM Fluor 488 A ⁇ 1-42
  • 1% NH 4 OH solution purchased from Anaspec.
  • Triton® X-100 and paraformaldehyde (PFA) were obtained from Sigma Aldrich.
  • Cyclo-phenylalanine-phenylalanine was purchased from Bachem.
  • a soluble version of the A ⁇ 1-42 peptide (A ⁇ 1-42 monomer) was prepared according to the A ⁇ 1-42 preparation manufacturer's recommendations (Anaspec). Lyophilized A ⁇ 1-42 peptide was dissolved in 1% NH 4 OH solution at a concentration of 2 mg/mL. The peptide solution was further diluted with DPBS to a final concentration of 1 mg/mL stock solution. Reconstituted peptides were aliquoted into several freezer vials and stored at -20°C. Rhodamine B-labeled synthetic A ⁇ 1-42 peptide (GL Biochem, Shanghai, China) was dissolved in cold hexafluoroisopropanal (HFIP) at a concentration of 1 mM.
  • HFIP cold hexafluoroisopropanal
  • DMSO dimethylsulfoxide
  • MEM minimal essential medium
  • SIM-A9 mouse microglial cells (ATCC CRL-3265) were maintained in DMEM/F12 supplemented with 10% FBS, 5% HS and 1% P/S.
  • SIM-A9 cells were removed from culture flasks, pelleted, and resuspended in serum-free DMEM/F12.
  • Cells were seeded on PDL-coated 24-well plates at a density of 200,000 cells/well and pretreated with Cyclo(Phe-Phe) for 24 hours at 37° C. in a humidified gas chamber containing 5% CO 2 .
  • the final treatment concentration of Cyclo(Phe-Phe) was 2.2 ⁇ g/mL.
  • BV-2 mouse microglial cells were maintained in MEM supplemented with 10% FBS, 1% sodium pyruvate and 1% P/S. Cells were co-treated with 11.05 ⁇ g/mL Cyclo(Phe-Phe) and 2 ⁇ M A ⁇ 1-42 oligomers for 16 h at 37° C. in a humidified gas chamber containing 5% CO 2 . Cyclo(Phe-Phe) was dissolved in hydrochloric acid (HCl) and added to MEM.
  • HCl hydrochloric acid
  • Phagocytosis Assay Adherent SIM-A9 microglia were pretreated with Cyclo(Phe-Phe) (2.2 ⁇ g/mL) for 24 h, rinsed once with serum-free DMEM/F12, and then serum-free DMEM/F12. A ⁇ 1-42 (monomer) was added at a concentration of 4.51 ⁇ g/mL in medium and incubated at 37° C. for 6 hours. At the end of the incubation period, the A ⁇ 1-42 containing medium was removed and the cells were gently rinsed three times with HBSS and twice with DPBS to remove extracellular A ⁇ 1-42 .
  • BV-2 cells co-treated with Cyclo(Phe-Phe) and A ⁇ 1-42 oligomers were fixed with 4% PFA and micrographs were taken.
  • flow cytometric analysis cells were washed twice with 2% FBS, centrifuged at 1000 rpm for 5 minutes and blocked with Fc-Block (BD Bioscience) for 30 minutes. Fluorescence data were analyzed using FlowJo software (Tree Star, Ashland, OR).
  • FIGS. 3 and 4 depict the effect results of Cyclo(Phe-Phe) in enhancing phagocytosis of amyloid ⁇ 1-42 oligomers are shown in FIGS. 3 and 4.
  • FIG. 3 depicts BV-2 microglia treated with A ⁇ 1-42 oligomers (vehicle control (VC)) and BV-2 microglia co-treated with Cyclo(Phe-Phe) and A ⁇ 1-42 oligomers (CFF).
  • 3A, 3B and 3C vehicle control (VC)
  • 3D, 3E and 3F Cyclo(Phe-Phe) treatment).
  • CFF Cyclo(Phe-Phe) treated group
  • CFF Cyclo(Phe-Phe) treated group
  • BV-2 microglia were treated with CFF and A ⁇ 1-42 oligomers for 16 hours.
  • Figures 3A and 3D show the cell densities observed by brightfield microscopy
  • Figures 3B and 3E show the presence of A ⁇ 1-42 peptide stained with rhodamine B
  • Figures 3C and 3F show the cells Merged images of Rhodamine B-stained A ⁇ 1-42 peptides and cells incorporated into .
  • CFF administration can significantly enhance the phagocytic activity of BV-2 cells incubated with A ⁇ 1-42 peptide oligomers. This was characterized by increased frequency of fluorescent cells and enhanced microglial mean fluorescence intensity (MFI) levels compared to untreated control cells (VC) (FIGS. 3 and 4).
  • MFI microglial mean fluorescence intensity
  • Cyclo(Phe-Phe) enhanced phagocytosis of amyloid ⁇ 1-42 monomers by SIM-A9 microglial cells and phagocytosis of amyloid ⁇ 1-42 oligomers by BV-2 microglial cells.
  • Amyloid precursor protein (APP) overexpression cell assay An in vitro assay was performed to investigate the effect of Cyclo(Phe-Phe) (CFF) on amyloid ⁇ accumulation.
  • the assay used H4 glioma cells overexpressing amyloid precursor protein wild-type with the Swedish double mutation K595N/M596L (H4-hAPP cells).
  • H4-hAPP cells H4 glioma cells overexpressing amyloid precursor protein wild-type with the Swedish double mutation K595N/M596L
  • H4-hAPP cells were obtained by stable transfection of human H4 glioma cell line with pAG3 vector containing human amyloid precursor protein 695 (APP695) with Swedish double mutation K595N/M596L.
  • the pAG3 vector is a modified pcDNA3 plasmid containing a hygromycin B resistance cassette with the transgene under the control of the fused CMV and chicken ⁇ -actin promoters.
  • H4-hAPP cells were maintained in Opti-MEM supplemented with 10% FCS, 1% P/S, 200 ⁇ g/mL hygromycin B and 2.5 ⁇ g/mL blasticidin S hydrochloride. . Cells were seeded in 96-well plates at a density of 25,000 cells/well and incubated overnight at 37°C in a humidified gas chamber containing 5% CO2 . The next day, H4-hAPP cells were treated with 22 mg/mL CFF. In the CFF treatment, CFF was added to the medium of H4-hAPP cells to 22 ⁇ g/mL, and the cells were incubated.
  • H4-hAPP cells were treated with 400 nM DAPT instead of CFF. After 24 hours of treatment, cell culture supernatants were collected for amyloid- ⁇ (A ⁇ ) analysis. H4-hAPP cells without CFF and DAPT treatment served as vehicle control and cell supernatants were collected.
  • a ⁇ amyloid- ⁇
  • Amyloid- ⁇ ELISA Assay Collected cell culture supernatants were diluted 1:10 and tested using the 6E10 Abeta Triplex Assay kit for human amyloid- ⁇ 1-38 (A ⁇ 1-38 ), human amyloid- ⁇ 1-40 (A ⁇ 1-40) . ), and human amyloid ⁇ 1-42 (A ⁇ 1-42 ) were analyzed. Multiplex assays were performed according to the manufacturer's instructions and plates were read on a Sector Imager 2400 (Meso Scale Discovery). Amyloid ⁇ concentrations were calculated with reference to a standard curve. The sensitivity of the multiplex kit was ⁇ 5 pg/mL.
  • FIG. 5 is a graph showing the concentration of amyloid ⁇ 1-38 in the culture supernatant of H4-hAPP cells.
  • FIG. 6 is a graph showing the concentration of amyloid ⁇ 1-40 in the culture supernatant of H4-hAPP cells.
  • FIG. 7 is a graph showing the concentration of amyloid ⁇ 1-42 in the culture supernatant of H4-hAPP cells.
  • CFF CFF-treated cells.
  • CFF suppressed the accumulation of A ⁇ 1-38 , A ⁇ 1-40 and A ⁇ 1-42 in H4-hAPP cells.
  • CFF has the effect of suppressing the accumulation of amyloid ⁇ 1-38 , amyloid ⁇ 1-40 and amyloid ⁇ 1-42 in H4-hAPP cells.

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WO2013021353A1 (en) * 2011-08-11 2013-02-14 Bar-Ilan University Surface modified proteinaceous spherical particles and uses thereof
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