WO2019198825A1

WO2019198825A1 - Prophylactic, therapeutic, or diagnostic drug for alzheimer's disease using microorganism-derived compound

Info

Publication number: WO2019198825A1
Application number: PCT/JP2019/016029
Authority: WO
Inventors: 治久井上; 孝之近藤
Original assignee: 国立大学法人京都大学
Priority date: 2018-04-13
Filing date: 2019-04-12
Publication date: 2019-10-17
Also published as: JPWO2019198825A1; JP7318948B2

Abstract

The present invention provides a prophylactic, therapeutic, or diagnostic drug for Alzheimer's disease using a microorganism-derived compound. Specifically provided are a prophylactic or therapeutic agent for Alzheimer's disease that includes at least one compound selected from the group consisting of Mer-A2026A, verrucarin A, kalafungin, concanamycin A, efomycin A, brefeldin A, eupenifeldin, elaiophylin, and boromycin, or a pharmaceutically acceptable salt thereof, and a diagnostic drug for Alzheimer's disease that includes a substance for detecting in a specimen: at least one compound selected from the group consisting of the aforementioned compounds, roridin A, leucanicidin, bafilomycin A1, and bafilomycin B1 or a pharmaceutically acceptable salt thereof; a microorganism that produces said compound or pharmaceutically acceptable salt thereof; or an extract of said microorganism.

Description

A preventive, therapeutic or diagnostic agent for Alzheimer's disease using a microbial compound

The present invention relates to a preventive, therapeutic or diagnostic agent for Alzheimer's disease using a microorganism-derived substance.

Alzheimer's disease (AD) is a type of dementia whose main symptoms are cognitive decline and personality changes. Characteristic features of Alzheimer's disease brain lesions include loss of neuronal degeneration and associated cerebral atrophy, frequent senile plaques, and frequent neurofibrillary tangles (NFT). Among these, senile plaques are known to be aggregated accumulation of amyloid β (Aβ) peptide. Aβ is a 38-43 amino acid peptide produced as a result of cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Among these, Aβ42 is known to have high aggregation ability and neurocytotoxicity, and it has been reported that an increase in Aβ42 / 40 ratio is observed in cells having a causative mutation of familial Alzheimer's disease (FAD). . For this reason, it is widely recognized that decreasing the amount of Aβ42 and the Aβ42 / 40 ratio is a key point for suppressing the onset of Alzheimer's disease.

It has been suggested that the onset of Alzheimer's disease contributes not only to the genome information possessed by individuals but also to bacterial flora consisting of microorganisms in the body called microbiomes. However, the detailed mechanism is not understood, and the knowledge about the microorganisms related to the onset of Alzheimer's disease and the microorganism-derived compounds related to the onset of Alzheimer's disease is not obtained.

Currently, there are several treatments for Alzheimer's disease, including donepezil, but no fundamental treatment has yet been found, and the structure and mechanism are unprecedented. There has been a long-awaited discovery of a new therapeutic agent having

In addition, it is known that the pathological changes of Aβ have already progressed before reaching mild cognitive impairment (MCI), and early detection and early treatment are considered necessary. It has been. However, the diagnostic agents currently on the market cannot sufficiently detect early pathological changes in Aβ, and there is a strong demand for the discovery of new diagnostic agents that can detect the pathological changes in Aβ early. It was.

By the way, the pathogenic cells induced by differentiation from patient-derived iPS cells (disease iPS cells) are expected to reproduce the patient's pathology in vitro, and thus are expected to be effective drug evaluation systems. Yes. Recent reports on human iPS cell-derived neurons emphasize the importance of human neurons as a tool for evaluating drug responsiveness (Non-Patent Documents 1 to 3).

As described above, in the treatment of Alzheimer, no satisfactory therapeutic agent has been found yet, and new drug discovery has been expected. The present invention aims at drug discovery with a compound having a new structure that has not been studied as an Alzheimer's therapeutic agent so far, and screens for microbial-derived compounds to find and provide a novel preventive or therapeutic agent for Alzheimer's disease. The purpose is to do. Another object of the present invention is to find and provide a diagnostic agent for Alzheimer's disease using a microorganism-derived compound.

The present inventors have conducted intensive research to solve the above-mentioned problems, and as a result of screening various microbial-derived compounds using nerve cells that have been induced to differentiate from iPS cells derived from Alzheimer's disease patients, they have been derived from some specific microorganisms. The compound was found to change the amount of Aβ42 and the Aβ42 / 40 ratio in the nerve cells, and the present invention was completed.

That is, the present invention relates to the following [1] to [16-2].
[1]
One or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Eliophilin, and Boromycin, or a pharmaceutically acceptable salt thereof An agent for preventing or treating Alzheimer's disease,
[2]
The agent according to [1], wherein the compound is one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof;
[3]
The agent according to [1], wherein the compound is Mer-A2026A or a pharmaceutically acceptable salt thereof;
[3-1]
The agent according to [1], wherein the compound is carafungin or a pharmaceutically acceptable salt thereof;
[4]
1 selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Elaophilin, and Boromycin in the manufacture of a preventive or therapeutic agent for Alzheimer's disease Use of more than one compound or a pharmaceutically acceptable salt thereof;
[4-1]
The use according to [4], wherein the compound is one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof;
[4-2]
The use according to [4], wherein the compound is Mer-A2026A or a pharmaceutically acceptable salt thereof;
[5]
One selected from the group consisting of Mer-A2026A, Belkaline A, Karafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Elaophilin, and Boromycin for the prevention or treatment of Alzheimer's disease Or a pharmaceutically acceptable salt thereof;
[5-1]
One or more compounds selected from the group consisting of Mer-A2026A and Belkaline A or a pharmaceutically acceptable salt thereof for the prevention or treatment of Alzheimer's disease;
[5-2]
Mer-A2026A or a pharmaceutically acceptable salt thereof for the prevention or treatment of Alzheimer's disease;
[5-3]
One or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Eliophilin, and Boromycin, or a pharmaceutically acceptable salt thereof A method of preventing or treating Alzheimer's disease, comprising administering to a patient a therapeutically effective amount of a salt of
[5-4]
The preventive or therapeutic method according to [5-3], wherein the compound is one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof;
[5-5]
The preventive or therapeutic method according to [5-3], wherein the compound is Mer-A2026A or a pharmaceutically acceptable salt thereof;
[6]
One or more compounds selected from the group consisting of eupeniferdin, elaiophilin, boromycin, Mer-A2026A, verkaline A, carafungin, conkanamycin A, efomycin A, and brefeldin A in a specimen, or a pharmaceutical thereof A diagnostic agent for Alzheimer's disease, comprising: a salt that is acceptable to the microorganism, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism;
[7]
A compound or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism is Eupenfeldin, elaiophyrin, boromycin , Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, and Brefeldin A, one or more compounds, or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically The diagnostic agent according to [6], which is an antibody that binds to a microorganism that produces an acceptable salt or an extract of the microorganism;
[8]
The diagnostic agent according to [6] or [7], wherein the compound is one or more compounds selected from the group consisting of eupenifeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof;
[9]
The diagnostic agent according to any one of [6] to [8], wherein the compound is Eupenfeldin or a pharmaceutically acceptable salt thereof;
[9-1]
One or more selected from the group consisting of eupeniferdin, elaiophyrin, boromycin, Mer-A2026A, verkaline A, carafungin, conkanamycin A, efomycin A, and brefeldin A in the manufacture of a diagnostic agent for Alzheimer's disease Or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or use of an antibody that binds to an extract of the microorganism;
[9-2]
The use according to [9-1], wherein the compound is one or more compounds selected from the group consisting of Eupenfeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof;
[9-3]
The use according to [9-1], wherein the compound is Eupenfeldin or a pharmaceutically acceptable salt thereof;
[10]
One or more selected from the group consisting of Eupenfeldin, Elaophilin, Boromycin, Mer-A2026A, Belkaline A, Karafungin, Conkanamycin A, Efomycin A, and Brefeldin A for diagnosing Alzheimer's disease A compound or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or an antibody that binds to an extract of the microorganism;
[10-1]
The antibody according to [10], wherein the compound is one or more compounds selected from the group consisting of Eupeniferin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof;
[10-2]
One or more compounds selected from the group consisting of eupeniferdin, elaiophilin, boromycin, Mer-A2026A, verkaline A, carafungin, conkanamycin A, efomycin A, and brefeldin A in a specimen, or a pharmaceutical thereof A method of diagnosing Alzheimer's disease, comprising a process for detecting a pharmaceutically acceptable salt, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism;
[10-3]
Producing one or more compounds selected from the group consisting of eupenifeldin, elaiophilin, and boromycin in a sample, or a pharmaceutically acceptable salt thereof, or the compound or a pharmaceutically acceptable salt thereof A method of diagnosing Alzheimer's disease comprising a process of detecting a microorganism or an extract of said microorganism;
[10-4]
Diagnosis of Alzheimer's disease comprising a process for detecting Eupeniferdin or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism in a specimen Method;
[11]
One or more compounds selected from the group consisting of loridine A, leucanicidine, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof, in a sample A diagnostic agent for Alzheimer's disease comprising a microorganism that produces a salt or a substance for detecting an extract of the microorganism;
[12]
A compound or a pharmaceutically acceptable salt thereof, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism is Loridine A, Leukanicidin, Bafilomycin A1, And one or more compounds selected from the group consisting of bafilomycin B1 or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism The diagnostic agent according to [11], which is an antibody that binds;
[13]
The diagnostic agent according to [11] or [12], wherein the compound is loridine A or a pharmaceutically acceptable salt thereof;
[13-1]
One or more compounds selected from the group consisting of loridine A, leucanicidine, bafilomycin A1, and bafilomycin B1 in the manufacture of a diagnostic agent for Alzheimer's disease, or a pharmaceutically acceptable salt thereof, the compound or its Use of a microorganism that produces a pharmaceutically acceptable salt, or an antibody that binds to an extract of said microorganism;
[13-2]
The use according to [13-1], wherein the compound is loridine A or a pharmaceutically acceptable salt thereof;
[14]
One or more compounds selected from the group consisting of loridine A, leucanicidine, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable salt thereof, the compound or a medicament thereof for diagnosing Alzheimer's disease An antibody that binds to a microorganism that produces a pharmaceutically acceptable salt, or an extract of said microorganism;
[14-1]
The antibody according to [14], wherein the compound is loridine A or a pharmaceutically acceptable salt thereof;
[15]
The specimen is selected from the group consisting of blood, plasma, serum, interstitial fluid, extravascular fluid, cerebrospinal fluid, synovial fluid, pleural fluid, lymph fluid, saliva, urine, and stool, [6] to [9] or [11] The diagnostic agent according to any one of [13];
[16]
One or more compounds selected from the group consisting of loridine A, leucanicidin, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable salt thereof, or the compound or a pharmaceutically acceptable salt thereof in a sample A method for diagnosing Alzheimer's disease comprising a process for detecting a microorganism that produces a salt or an extract of said microorganism;
[16-1]
A method for diagnosing Alzheimer's disease comprising a process for detecting loridine A or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism in a specimen;
[16-2]
The specimen is selected from the group consisting of blood, plasma, serum, interstitial fluid, extravascular fluid, cerebrospinal fluid, synovial fluid, pleural fluid, lymph fluid, saliva, urine, and stool, [10-2] to [10 -4] or the diagnostic method according to any one of [16] to [16-1].

The present invention also relates to the following [17] to [45].
[17]
One or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Eliophilin, and Boromycin, or a pharmaceutically acceptable salt thereof An agent for changing the amount of Aβ42 and / or the Aβ42 / 40 ratio,
[18]
An agent for reducing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof;
[19]
An agent for reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio, comprising Mer-A2026A or a pharmaceutically acceptable salt thereof;
[20]
An agent for increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising one or more compounds selected from the group consisting of eupeniferzin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof ;
[21]
An agent for increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio, comprising Eupenfeldin or a pharmaceutically acceptable salt thereof;
[22]
Mer-A2026A, Belkaline A, Carahungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupeniferdin, Elaophylline, and Boromomycin in the manufacture of agents for changing the amount of Aβ42 and / or the ratio of Aβ42 / 40 Use of one or more compounds selected from the group consisting of: or a pharmaceutically acceptable salt thereof;
[23]
Use of one or more compounds selected from the group consisting of Mer-A2026A and velkaline A or a pharmaceutically acceptable salt thereof in the manufacture of an agent for reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[24]
Use of Mer-A2026A or a pharmaceutically acceptable salt thereof in the manufacture of an agent for reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[25]
One or more compounds selected from the group consisting of eupeniferdin, elaiophyrin, and boromycin, or a pharmaceutically acceptable product thereof, in the manufacture of an agent for increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio Use of salt;
[26]
Use of Eupeniferdin or a pharmaceutically acceptable salt thereof in the manufacture of an agent for increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[27]
From the group consisting of Mer-A2026A, Belkaline A, Karafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupeniferdin, Elaophilin, and Boromycin for varying Aβ42 amount and / or Aβ42 / 40 ratio One or more selected compounds or pharmaceutically acceptable salts thereof;
[28]
One or more compounds selected from the group consisting of Mer-A2026A and Velkaline A or a pharmaceutically acceptable salt thereof for reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[29]
Mer-A2026A or a pharmaceutically acceptable salt thereof for reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[30]
One or more compounds selected from the group consisting of Eupenfeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof, for increasing Aβ42 amount and / or Aβ42 / 40 ratio;
[31]
Eupenifeldin or a pharmaceutically acceptable salt thereof for increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[32]
One or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Eliophilin, and Boromycin, or a pharmaceutically acceptable salt thereof A method of altering the amount of Aβ42 and / or the Aβ42 / 40 ratio, comprising administering to a patient an effective amount of a salt of
[33]
Decreasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising administering to a patient an effective amount of one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof How to make;
[34]
A method of reducing the amount of Aβ42 and / or the Aβ42 / 40 ratio comprising administering to a patient an effective amount of Mer-A2026A or a pharmaceutically acceptable salt thereof;
[35]
Aβ42 amount and / or Aβ42 / 40 ratio comprising adding to the specimen one or more compounds selected from the group consisting of eupenifeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof. How to increase
[36]
A method of increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising adding Eupenfeldin or a pharmaceutically acceptable salt thereof to the specimen;
[37]
Increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio, comprising one or more compounds selected from the group consisting of loridine A, leukanicidin, bafilomycin A1, and bafilomycin B1, or pharmaceutically acceptable salts thereof An agent for
[38]
An agent for increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising loridine A or a pharmaceutically acceptable salt thereof;
[39]
One or more compounds selected from the group consisting of loridine A, leukanicidin, bafilomycin A1, and bafilomycin B1 in the manufacture of an agent for increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, or a pharmaceutical thereof Use of acceptable salts;
[40]
Use of loridine A or a pharmaceutically acceptable salt thereof in the manufacture of an agent for increasing the amount of Aβ42 and / or the Aβ42 / 40 ratio;
[41]
One or more compounds selected from the group consisting of loridine A, leukanicidin, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable thereof, for increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40 salt;
[42]
Use of loridine A or a pharmaceutically acceptable salt thereof to increase the amount of Aβ42 and / or the ratio of Aβ42 / 40;
[43]
Aβ42 amount and / or comprising adding one or more compounds selected from the group consisting of loridine A, leukanicidin, bafilomycin A1, and bafilomycin B1 or a pharmaceutically acceptable salt thereof to the specimen. A method of increasing the Aβ42 / 40 ratio;
[44]
A method of increasing the amount of Aβ42 and / or the ratio of Aβ42 / 40, comprising adding Loridine A or a pharmaceutically acceptable salt thereof to the specimen;
[45]
The specimen is selected from the group consisting of blood, plasma, serum, interstitial fluid, extravascular fluid, cerebrospinal fluid, synovial fluid, pleural fluid, lymph fluid, saliva, urine, and stool, [35], [36], [43] The method according to any one of [44].

The microorganism-derived compound used in the present invention has an effect of changing the amount of Aβ42 and the ratio of Aβ42 / 40, and thus is useful for the prevention, treatment or diagnosis of Alzheimer's disease. In particular, the prophylactic or therapeutic compound found in the present invention is a compound of a structural group that has not been known as a therapeutic agent for Alzheimer's disease, and is expected as a drug that has overcome the problems of existing therapeutic agents for Alzheimer's disease. . Moreover, the diagnostic compound found in the present invention is a compound of a structural group that has been unknown as an Alzheimer's disease biomarker so far, and is expected as a compound that overcomes the problems of existing Alzheimer's disease biomarkers.

The first screening results using cortical neurons derived from iPS cells derived from a familial Alzheimer's disease patient having the G384A mutation of PSEN1 are shown. The vertical axis shows the rate of change of Aβ40, Aβ42, and Aβ42 / 40 ratio with respect to DMSO control when 1 μM or 50 nM of each compound is added. The horizontal axis indicates the compound number. The second screening results using cortical neurons derived from iPS cells derived from a familial Alzheimer's disease patient having the G384A mutation of PSEN1 are shown. The correlation plot of the 1st screening and the 2nd screening is shown about the test done with the compound of 1 micromol using the cerebral cortex nerve cell induced | guided | derived from the iPS cell derived from the familial Alzheimer's disease patient who has the G384A mutation of PSEN1. The vertical axis represents the value in the first screening, and the horizontal axis represents the value in the second screening. The screening result using the cerebral cortical nerve cell induced | guided | derived from the iPS cell derived from a sporadic Alzheimer's disease patient is shown. The vertical axis shows the rate of change of Aβ40, Aβ42, and Aβ42 / 40 ratio with respect to DMSO control when 1 μM or 50 nM of each compound is added. The horizontal axis indicates the compound number. The results of plotting the Aβ42 / 40 ratio in the screening using cortical neurons derived from iPS cells derived from familial and sporadic Alzheimer's disease for each of the microorganism-derived compounds screened are shown. The vertical axis shows the rate of change of Aβ42 / 40 ratio to DMSO when using cerebral cortical neurons derived from sporadic Alzheimer's disease iPS cells, and the horizontal axis is derived from familial Alzheimer's disease iPS cells. The change rate with respect to DMSO of A (beta) 42/40 ratio at the time of using a cerebral cortex nerve cell is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of leucanicidine (compound 01) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of bafilomycin A1 (compound 02) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependence of Loridine A (compound 03) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of bafilomycin B1 (compound 04) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of carahungin (compound 05) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, it shows the concentration dependency of concanamycin A (compound 06) on toxicity. FIG. 6 shows the concentration dependency of vercarin A (compound 07) on Aβ40 and Aβ42 production, Aβ42 / 40 ratio, and toxicity using cerebral cortical neurons derived from iPS cells derived from a familial Alzheimer's disease patient. Two graphs with different Y-axis scales are shown for the same data. FIG. 5 shows the concentration dependency of verkaline A (compound 07) on Aβ40 and Aβ42 production, Aβ42 / 40 ratio, and toxicity using cerebral cortical neurons derived from iPS cells derived from a sporadic Alzheimer's disease patient. Two graphs with different Y-axis scales are shown for the same data. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependence of Eupenfeldin (compound 08) on toxicity is shown. The concentration dependence of Mer-A2026A (compound 09) on Aβ40 and Aβ42 production, Aβ42 / 40 ratio, and toxicity using cerebral cortical neurons derived from iPS cells derived from familial Alzheimer's disease patients is shown. Two graphs with different Y-axis scales are shown for the same data. Shows the concentration dependence of Mer-A2026A (compound 09) on Aβ40 and Aβ42 production, Aβ42 / 40 ratio, and toxicity using cerebral cortical neurons derived from iPS cells derived from sporadic Alzheimer's disease patients . Two graphs with different Y-axis scales are shown for the same data. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependence of efomycin A (compound 10) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of Brefeldin A (compound 11) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of elaiophyrin (compound 12) on toxicity is shown. Aβ40 and Aβ42 production, Aβ42 / 40 ratio, using cerebral cortex neurons derived from iPS cells from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells from sporadic Alzheimer's disease patients, In addition, the concentration dependency of boromycin (compound 13) on toxicity is shown.

The microorganism-derived compound used in the present invention is useful for the prevention, treatment or diagnosis of Alzheimer's disease. As used herein, the term “Alzheimer's disease” includes familial Alzheimer's disease (FAD) and sporadic Alzheimer's disease (SAD). In one embodiment, the microorganism-derived compound used in the present invention is used for prevention, treatment or diagnosis of familial Alzheimer's disease. In another embodiment, the microorganism-derived compound used in the present invention is used for prevention, treatment or diagnosis of sporadic Alzheimer's disease.

Prophylactic or therapeutic agent The prophylactic or therapeutic agent of the present invention comprises carafungin (CAS No. 11048-5-0; molecular weight 300.3), conkanamycin A (CAS No. 80890-47-7; molecular weight 866.1). ), Verrucarin A (CAS number 3148-09-2; molecular weight 502.6), Eupenfeldin (CAS number 151804-35-1; molecular weight 548.7), Mer-A2026A (CAS number 144357) -08-4; molecular weight 413.6), efomycin A; CAS number 106387-82-0; molecular weight 1039.3), brefeldin A; CAS number 20350-15-6; molecule 280.4), elaiophylin (CAS number 37318-06-2; molecular weight 1025.3), and boromycin (CAS number 34524-20-4; molecular weight 879.9). Or one or more pharmaceutically acceptable salts thereof (hereinafter also referred to as “components of the present invention”).

The compound selected from the group consisting of carafungin, conkanamycin A, verkaline A, eupeniferzin, Mer-A2026A, efomycin A, brefeldin A, elaophilin, and boromycin or a pharmaceutically acceptable salt thereof is Aβ42. Since it has the effect of changing the amount and the Aβ42 / 40 ratio, it can be used for the prevention or treatment of Alzheimer's disease. These may be used alone or in combination of two or more. The compound used for the prevention or treatment of Alzheimer's disease is preferably one or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Karafungin, and Conkanamycin A, or a pharmaceutically acceptable salt thereof. More preferred is one or more compounds selected from the group consisting of -A2026A and velcarine A, or a pharmaceutically acceptable salt thereof, and Mer-A2026A or a pharmaceutically acceptable salt thereof is particularly preferred.

The component of the present invention may be a commercially available product, a product produced from a commercially available product by a known method, or a product extracted from microorganisms. The preventive or therapeutic agent in the present invention may contain the component of the present invention itself, or may contain a microorganism that produces the component of the present invention. In the prevention or treatment method according to the present invention, the component of the present invention itself may be administered, or a microorganism producing the component of the present invention may be administered. The microorganism is not particularly limited as long as it can be easily obtained by those skilled in the art and produces at least one of the components of the present invention.

The component of the present invention may exist in the form of a tautomer or a mixture thereof. The component of the present invention may exist in the form of stereoisomers such as enantiomers and diastereomers, or a mixture thereof. When the components of the present invention are obtained in the form of diastereomers or enantiomers, these may be separated by conventional methods well known in the art, such as chromatography and fractional crystallization.

The component of the present invention is a compound labeled with an isotope (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³² P, ³⁵ S, or ¹²⁵ I) and a deuterium converter. Is included.

The component of the present invention can exist in a free form or a pharmaceutically acceptable salt form. Examples of pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, formate, acetate, propionate, fumarate, Oxalate, malonate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, maleate, lactate, malate, tartrate, citrate, and trifluoroacetate Acid addition salts such as: lithium salts, potassium salts, calcium salts, magnesium salts, sodium salts, zinc salts, and aluminum salts; and ammonium salts, diethanolamine salts, ethylenediamine salts, triethanolamine salts, and triethylamine salts And base addition salts. The pharmaceutically acceptable salt includes any of its intramolecular salts and adducts, solvates or hydrates thereof.

In one embodiment, the present invention provides the use of a component of the present invention in the manufacture of an agent for preventing or treating Alzheimer's disease.

In another embodiment, the present invention provides a method for preventing or treating Alzheimer's disease comprising administering to a patient a therapeutically effective amount of a component of the present invention.

In another embodiment, the present invention provides a component of the present invention for the prevention or treatment of Alzheimer's disease.

The term “patient” in the present specification is an individual to be prevented, treated, or diagnosed, and is preferably a mammal, more preferably a human.

The component of the present invention can be administered either orally or parenterally, alone or mixed with a pharmaceutically acceptable additive. The pharmaceutically acceptable additive may be an additive commonly used in the art, such as a binder (such as syrup, gum arabic, gelatin, sorbit, tragacanth, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone). , Excipients (such as lactose, sucrose, corn starch, potassium phosphate, sorbit, and glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol, and silica), disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium) , And potato starch), emulsifiers (such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters), stabilizers (such as methyl paraben and pro Ruparaben etc.), and the like diluting agents. The dosage form of the preparation of the present invention is not particularly limited, and tablets, pills, granules, capsules, powders, syrups, emulsions, suspensions, injections, inhalants, suppositories, etc. It can be used as a conventional pharmaceutical preparation.

The present invention component may be formulated as only one kind, or may be formulated by combining two or more kinds. When two or more components are combined, they may be formulated as a single preparation or may be formulated as separate preparations. When formulating two or more components of the present invention as separate preparations, the dosage form of each preparation may be the same or different.

The component of the present invention may be used in combination with other Alzheimer's disease therapeutic agents. Examples of other Alzheimer's disease therapeutic agents include donepezil, memantine, galantamine, and rivastigmine.

The therapeutically effective amount of each component of the present invention varies depending on the type of component, administration method, patient age, body weight, condition and the like, but in the case of oral administration, 0.1 to 1000 mg per dose, Preferably, it can be 0.5 to 500 mg / kg, and in the case of parenteral administration, it can be 0.01 to 100 mg per day, preferably 0.05 to 50 mg / kg once a day. Or it can be administered several times. Where the formulations of the present invention contain more than one component, they can be administered simultaneously or separately.

Diagnostic Agent and Diagnostic Method Components of the present invention, and leucanicidin (CAS number 91021-66-8; molecular weight 783.0), bafilomycin A1 (bafilomycin A1; CAS number 88899-55-2; molecular weight 622.8), A compound selected from the group consisting of loridine A (CAS number 14729-29-4; molecular weight 532.6) and bafilomycin B1 (CAS number 88899-56-3; molecular weight 816.0) Alternatively, a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the biomarker of the present invention”) has an action of changing the amount of Aβ42 or the Aβ42 / 40 ratio, and thus can be used for diagnosis of Alzheimer's disease and the like. In the component of the present invention, the compound to be diagnosed is preferably one or more compounds selected from the group consisting of eupenifeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof. Peniferin or a pharmaceutically acceptable salt thereof is more preferred. In the biomarker of the present invention, loridine A or a pharmaceutically acceptable salt thereof is preferable as the compound to be diagnosed. The diagnostic agent for Alzheimer's disease of the present invention contains a substance for detecting a component of the present invention or a biomarker of the present invention, a microorganism producing the component or biomarker, or an extract of the microorganism in a sample. The microorganism is not particularly limited as long as it is easily available to those skilled in the art and produces at least one of the component of the present invention or the biomarker of the present invention. The microorganism extract is not particularly limited as long as it is a substance other than the component of the present invention or the biomarker of the present invention present in the microorganism and is a substance characteristic of the microorganism. Examples thereof include DNA and RNA characteristic of microorganisms. In one embodiment, the diagnostic agent for Alzheimer's disease of the present invention comprises a substance for detecting the component of the present invention or the biomarker of the present invention in a specimen.

The term “specimen” in the present specification means a biological sample collected from a patient to be diagnosed, such as blood, plasma, serum, interstitial fluid, extravascular fluid, cerebrospinal fluid, synovial fluid, pleural fluid, Examples include lymph, saliva, urine, and stool. You may use these in combination of 2 or more type. Preferably, blood, plasma, serum, or cerebrospinal fluid is used.

The substance for detecting the component of the present invention or the biomarker of the present invention, the microorganism producing the component or biomarker, or the extract of the microorganism is not particularly limited, and for example, a receptor and an antibody can be used. An antibody is preferable, and an antibody that specifically binds to a component of the present invention or a biomarker of the present invention, a microorganism that produces the component or biomarker, or an extract of the microorganism is more preferable. Moreover, the method of detecting the component of the present invention or the biomarker of the present invention, the microorganism producing the component or biomarker, or the extract of the microorganism is not particularly limited. When using the component of the present invention or the biomarker of the present invention, a microorganism producing the component or biomarker, or an antibody against the extract of the microorganism, an immunological method such as enzyme-linked immunosorbent assay (ELISA) is used. A component of the present invention or a biomarker of the present invention, a microorganism producing the component or biomarker, or an extract of the microorganism can be detected, and preferably an ELISA using a direct adsorption method, a sandwich method, or a competitive method is used. Used.

For example, the component of the present invention or the biomarker of the present invention, the microorganism producing the component or the biomarker, or the extract of the microorganism produces the antibody as the component of the present invention or the biomarker of the present invention, the component or biomarker. After binding to a microorganism or an extract of the microorganism, the component of the present invention or the biomarker of the present invention bound to the antibody, the microorganism producing the component or the biomarker, or the extract of the microorganism is the antibody. Another antibody (primary detection antibody) and detected by an antibody labeled with a labeling substance, or detected by an antibody bound to the primary detection antibody and labeled with a labeling substance (secondary detection antibody). As the labeling substance, a substance well known in the art can be used. For example, radioisotopes such as ³² P, ¹⁴ C, and ¹²⁵ I, and enzymes such as horseradish peroxidase can be used. When ELISA is used, it is preferable to use an enzyme such as horseradish peroxidase as a labeling substance. In this case, the fluorescence or chromogenic substrate of the enzyme such as 3,3 ′, 5,5′-tetramethylbenzidine (TMB) is added, and the fluorescence or chromogenicity is detected using a fluorimeter or the like. Inventive components or biomarkers of the present invention, microorganisms producing the components or biomarkers, or extracts of the microorganisms can be detected.

The component of the present invention or the biomarker of the present invention, the microorganism producing the component or biomarker, or the antibody against the extract of the microorganism comprises the component of the present invention or the biomarker of the present invention, the microorganism producing the component or the biomarker, Alternatively, any antibodies can be used as long as they can specifically bind to the microorganism extract, and examples include human antibodies, humanized antibodies, chimeric antibodies, and non-human antibodies such as mouse antibodies. It may be an antibody or a monoclonal antibody. The antibody can be produced by a method known in the art, for example, by a known method using a hybridoma of antibody-producing cells and myeloma cells.

In one embodiment, the present invention provides a diagnostic agent for Alzheimer's disease comprising an ingredient of the invention or a biomarker of the invention, a microorganism that produces the ingredient or biomarker, or an antibody that binds to an extract of the microorganism. . In another embodiment, the present invention provides a diagnostic agent for Alzheimer's disease comprising an antibody that binds to a component of the present invention or a biomarker of the present invention. The diagnostic agent may be in the form of a kit. In one embodiment, the diagnostic agent may be a diagnostic agent for ELISA measurement, for example, a solid phase such as a microplate or beads adsorbed with the antibody; a component of the present invention or a biomarker of the present invention, the component or biochemical A primary detection antibody that binds to a microorganism that produces a marker, or an extract of the microorganism, and recognizes an epitope different from the antibody; a secondary detection antibody that binds to the primary detection antibody and is labeled with an enzyme such as horseradish peroxidase Secondary detection antibody; chromogenic substrate of the enzyme such as TMB (3,3 ′, 5,5′-tetramethylbenzidine); dilution buffer; washing buffer and the like as appropriate.

By comparing the concentration of the component of the present invention or the biomarker of the present invention, the microorganism producing the component or biomarker, or the extract of the microorganism detected with the above diagnostic agent with a reference value, Alzheimer's disease Diagnosis can be made. The reference value is appropriately determined by a doctor, clinician, veterinarian or the like who has ordinary knowledge in the technical field. The component of the present invention or the biomarker of the present invention, the microorganism producing the component or biomarker, or the extract of the microorganism may be detected alone, but the diagnosis can be made by detecting a combination of two or more. Accuracy can be improved.

In one embodiment, the present invention provides the use of a component of the present invention or a biomarker of the present invention, a microorganism producing the component or biomarker, or a substance that binds to an extract of the microorganism in the manufacture of a diagnostic agent for Alzheimer's disease. I will provide a. In another embodiment, the present invention provides the use of an antibody that binds to a component of the present invention or a biomarker of the present invention, a microorganism that produces the component or biomarker, or an extract of the microorganism in the manufacture of a diagnostic agent for Alzheimer's disease. I will provide a. In another embodiment, the invention provides the use of a substance that binds to a component of the invention or a biomarker of the invention in the manufacture of a diagnostic for Alzheimer's disease. In another embodiment, the present invention provides the use of an antibody that binds to a component of the present invention or a biomarker of the present invention in the manufacture of a diagnostic for Alzheimer's disease.

In one embodiment, the invention provides a substance that binds to a component of the invention or a biomarker of the invention, a microorganism that produces the component or biomarker, or an extract of the microorganism, for diagnosing Alzheimer's disease. . In another embodiment, the invention provides an antibody that binds to a component of the invention or a biomarker of the invention, a microorganism that produces the component or biomarker, or an extract of the microorganism, for diagnosing Alzheimer's disease. . In another embodiment, the present invention provides a substance that binds to a component of the present invention or a biomarker of the present invention for diagnosing Alzheimer's disease. In another embodiment, the invention provides an antibody that binds to a component of the invention or a biomarker of the invention for diagnosing Alzheimer's disease.

In one embodiment, the present invention provides a method for diagnosing Alzheimer's disease, comprising a process for detecting a component of the present invention or a biomarker of the present invention, a microorganism producing the component or biomarker, or an extract of the microorganism in a sample. I will provide a. In another embodiment, the present invention provides a method for diagnosing Alzheimer's disease comprising a process for detecting a component of the present invention or a biomarker of the present invention in a specimen.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the following examples are provided for the purpose of explaining the present invention, and do not limit the present invention. In addition, in an Example, each term shall have the meaning normally used in the said technical field.

Example 1
Screening using cerebral cortical neurons derived from iPS cells derived from a familial Alzheimer's disease patient having the G384A mutation of PSEN1 Compound screening was performed according to the method described in WO2017 / 115873A1. That is, cerebral cortical neurons were prepared using iPS cells introduced with human Neurogenin 2 gene (NGN2) linked to a doxycycline-inducible promoter using PiggyBac. iPS cells are described in Okita K et al. , Nature. 2007, vol. 448, pp 313-317. NGN2 gene was introduced into these iPS cells, and doxycycline was added to allow transient expression for 5 days. As iPS cells used for performing high-throughput screening (HTS), iPS cells derived from familial Alzheimer's disease (FAD) patients having PSEN1 G384A mutation with high Aβ42 / 40 ratio and sporadic Alzheimer's disease (SAD) patients IPS cells were selected and cerebral cortical neurons were prepared.

Subsequently, using a cerebral cortical neuron derived from iPS cells derived from a familial Alzheimer's disease patient, screening was performed for a 123-organism-derived compound library described in Table 1 provided by Japan Microbiopharma Co., Ltd. And searched for preventive, therapeutic, or diagnostic agents for Alzheimer's disease.

10 μL of each microorganism-derived compound diluted to 1 μM or 50 nM with DMSO was added to 100,000 cerebral cortical neurons dispensed in a 96-well plate, respectively, and cultured at 37 ° C. After 48 hours, the culture supernatant was collected, and the production amounts of Aβ40 and Aβ42 in the supernatant were measured by the ECL-ELISA method. Further, the Aβ42 / 40 ratio was calculated from the measured values of Aβ40 and Aβ42 obtained. 0.1% v / v DMSO was used as a negative control, 1 μM β-secretase inhibitor IV (BSI) was used as a positive control to reduce Aβ40 or Aβ42, and 1 μM JNJ-40418677 (GSM) as a positive control to reduce the Aβ42 / 40 ratio. ) Was used. The screening results obtained using cerebral cortical neurons derived from iPS cells derived from a familial Alzheimer's disease patient having the G384A mutation of PSEN1 are shown in FIG. In addition, Table 2 and Table 3 show the values of the component of the present invention and the biomarker of the present invention, respectively.

Further, a second screening was performed to examine the reproducibility of the screening. The results are shown in FIG. Further, Table 4 and Table 5 show the values of the component of the present invention and the biomarker of the present invention, respectively. Further, FIG. 3 shows a correlation plot of the first screening and the second screening for the test conducted with 1 μM compound.

Example 2
Screening using cerebral cortical neurons derived from iPS cells derived from sporadic Alzheimer's disease patients Same as Example 1 except that cerebral cortical neurons derived from iPS cells derived from sporadic Alzheimer's disease patients were used. Screening was performed by the method. The results are shown in FIG. Further, Table 6 and Table 7 show the values of the component of the present invention and the biomarker of the present invention, respectively. Furthermore, the results of plotting the Aβ42 / 40 ratio in the second screening in Example 1 and the Aβ42 / 40 ratio in the screening in Example 2 for each microorganism-derived compound are shown in FIG. The names of microorganism-derived compounds that are at risk for sporadic Alzheimer's disease with a particularly high rate of change and the names of microorganism-derived compounds that are therapeutic agents for sporadic Alzheimer's disease are shown.

As described above, a compound selected from the group consisting of carafungin, conkanamycin A, verkaline A, eupeniferdin, Mer-A2026A, efomycin A, brefeldin A, elaiophilin, and boromycin is a patient with familial Alzheimer's disease In cerebral cortical neurons derived from iPS cells of origin, Aβ42 / 40 was significantly altered compared to DMSO, especially in studies performed with 1 μM compound. Carafungin also significantly reduced Aβ42 / 40 in cerebral cortical neurons derived from iPS cells from sporadic Alzheimer's disease patients. Conkanamycin A and Belkaline A significantly reduced Aβ42 / 40 even at low concentrations (50 nM) in cerebral cortical neurons derived from iPS cells derived from familial Alzheimer's disease patients. Therefore, a compound selected from the group consisting of carafungin, conkanamycin A, verkaline A, eupeniferdine, Mer-A2026A, efomycin A, brefeldin A, elaophilin, and boromycin is used for the prevention or treatment of Alzheimer's disease, etc. It was shown to be useful.

A compound selected from the group consisting of leucanicidin, bafilomycin A1, loridine A, and bafilomycin B1 is particularly useful in cerebral cortical neurons derived from iPS cells from sporadic Alzheimer's disease patients compared to DMSO. Aβ42 / 40 was significantly increased. Accordingly, it has been shown that a compound selected from the group consisting of leucanicidin, bafilomycin A1, loridine A, and bafilomycin B1 is useful for diagnosis of Alzheimer's disease, particularly sporadic Alzheimer's disease.

Example 3
Concentration-dependent evaluation of the component of the present invention or the biomarker compound of the present invention About the component of the present invention or the compound of the biomarker of the present invention, cerebral cortical neurons and sporadic Alzheimer derived from iPS cells derived from familial Alzheimer's disease patients Using cerebral cortical neurons derived from iPS cells derived from disease patients, the concentration dependence of Aβ production and cytotoxicity was evaluated.

For cerebral cortex neurons derived from iPS cells derived from familial Alzheimer's disease patients and cerebral cortex neurons derived from iPS cells derived from sporadic Alzheimer's disease patients, DMSO addition group as a negative control and dissolved in DMSO Aβ40 and Aβ42 production amount, Aβ42 / 40 ratio under the conditions of a total of 8 groups of each compound addition group (0.32 nM, 1.6 nM, 8 nM, 40 nM, 0.2 μM, 1 μM, and 5 μM) Concentration dependence for (Aβ42 / 40 ratio) as well as toxicity was evaluated. Measurement of the amount of Aβ in the culture supernatant (ECL-ELISA method) was evaluated using the same method as the screening in Examples 1 and 2. Toxicity was evaluated by measuring adenylate kinase activity in the culture supernatant using ToxiLight ™ (Lonza). For each compound, the DMSO addition group, which is a negative control, was set to 1, and the degree of change (Fold change (vs. DMSO control)) was plotted for each different concentration. The results are shown in FIGS. 6-1 to 6-13. In these figures, for Aβ variation, the fold change with respect to DMSO control is shown on the left Y-axis (Fold change of Aβ specifications (vs. DMSO control)), and for toxicity, fold change with respect to DMSO control is shown. Is shown on the right Y axis (Fold change of toxicity (vs. DMSO control)). In the x-axis drug concentration (Drug concentration (M)) in FIGS. 6-1 to 6-13, a numerical value such as “−10” indicates an index. For example, “−10” indicates a concentration of “10 ⁻¹⁰ ”. (M) ".

As is apparent from FIGS. 6-7-1, 6-7-2, 6-9-1, and 6-9-2, familial Alzheimer's for Verkaline A (compound 07) and Mer-A2026A (compound 09) In a concentration range (0.32 to 40 nM) in which no toxicity is observed in cerebral cortex neurons derived from iPS cells derived from disease patients and / or cerebral cortex neurons derived from iPS cells derived from sporadic Alzheimer's disease patients Also showed an effect of reducing the amount of Aβ42. In addition, as is clear from FIGS. 6-8, 6-12, and 6-13, familial Alzheimer's disease for Eupenfeldin (compound 08), elaiophyrin (compound 12), and boromycin (compound 13). In both cerebral cortical neurons derived from iPS cells derived from patients and cerebral cortical neurons derived from iPS cells derived from sporadic Alzheimer's disease patients, Aβ42 production was observed particularly in the low concentration range (0.32 to 8 nM). An increase was seen, indicating that it can be a factor of Aβ42 accumulation in the brain that causes Alzheimer's disease.

Since the microorganism-derived compound used in the present invention has an action of changing the amount of Aβ42 and the Aβ42 / 40 ratio, it can be used for prevention, treatment or diagnosis of Alzheimer's disease.

Claims

One or more compounds selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Eliophilin, and Boromycin, or a pharmaceutically acceptable salt thereof Or a preventive or therapeutic agent for Alzheimer's disease.
The agent according to claim 1, wherein the compound is one or more compounds selected from the group consisting of Mer-A2026A and Velkaline A, or a pharmaceutically acceptable salt thereof.
The agent according to claim 1, wherein the compound is Mer-A2026A or a pharmaceutically acceptable salt thereof.
1 selected from the group consisting of Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupeniferdin, Elaophilin, and Boromycin in the manufacture of a preventive or therapeutic agent for Alzheimer's disease Use of more than one compound or pharmaceutically acceptable salt thereof.
One selected from the group consisting of Mer-A2026A, Belkaline A, Karafungin, Conkanamycin A, Efomycin A, Brefeldin A, Eupenfeldin, Elaophilin, and Boromycin for the prevention or treatment of Alzheimer's disease Or a pharmaceutically acceptable salt thereof.
One or more compounds selected from the group consisting of eupeniferdin, elaiophilin, boromycin, Mer-A2026A, verkaline A, carafungin, conkanamycin A, efomycin A, and brefeldin A in a specimen, or a pharmaceutical thereof A diagnostic agent for Alzheimer's disease, comprising: a salt that is acceptable to the microorganism, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism.
A compound or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism is Eupenfeldin, elaiophyrin, boromycin , Mer-A2026A, Belkaline A, Carafungin, Conkanamycin A, Efomycin A, and Brefeldin A, one or more compounds, or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically The diagnostic agent according to claim 6, which is a microorganism that produces an acceptable salt or an antibody that binds to an extract of the microorganism.
The diagnostic agent according to claim 6 or 7, wherein the compound is one or more compounds selected from the group consisting of Eupenfeldin, elaiophilin, and boromycin, or a pharmaceutically acceptable salt thereof.
The diagnostic agent according to any one of claims 6 to 8, wherein the compound is Eupenfeldin or a pharmaceutically acceptable salt thereof.
One or more selected from the group consisting of Eupenfeldin, Elaophilin, Boromycin, Mer-A2026A, Belkaline A, Karafungin, Conkanamycin A, Efomycin A, and Brefeldin A for diagnosing Alzheimer's disease An antibody that binds to a compound or a pharmaceutically acceptable salt thereof, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism.
One or more compounds selected from the group consisting of loridine A, leucanicidine, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof, in a sample A diagnostic agent for Alzheimer's disease comprising a microorganism that produces a salt or a substance for detecting an extract of the microorganism.
A compound or a pharmaceutically acceptable salt thereof, a microorganism that produces the compound or a pharmaceutically acceptable salt thereof, or a substance for detecting an extract of the microorganism is Loridine A, Leukanicidin, Bafilomycin A1, And one or more compounds selected from the group consisting of bafilomycin B1 or a pharmaceutically acceptable salt thereof, a microorganism producing the compound or a pharmaceutically acceptable salt thereof, or an extract of the microorganism The diagnostic agent according to claim 11, which is an antibody that binds.
The diagnostic agent according to claim 11 or 12, wherein the compound is loridine A or a pharmaceutically acceptable salt thereof.
One or more compounds selected from the group consisting of loridine A, leucanicidine, bafilomycin A1, and bafilomycin B1, or a pharmaceutically acceptable salt thereof, the compound or a medicament thereof for diagnosing Alzheimer's disease An antibody that binds to a microorganism that produces a pharmaceutically acceptable salt or an extract of the microorganism.
The specimen is selected from the group consisting of blood, plasma, serum, interstitial fluid, extravascular fluid, cerebrospinal fluid, synovial fluid, pleural fluid, lymph fluid, saliva, urine, and stool. 14. The diagnostic agent according to any one of 13.