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November 24, 2017

iPSC trials and informatics find new drugs for Alzheimer's disease

CiRA researchers have conducted a new approach for discovering drugs to treat Alzheimer's disease.

By screening and chemoinformatics of existing drugs, they show a cocktail of three drugs reverses the molecular indications of Alzheimer's disease in an in vitro trial using multiple patients' neurons. The chemical structures of the drugs suggest independent modes of action that together give a synergistic effect.

At the molecular level, Alzheimer's disease is associated with the formation of amyloid β (Aβ) plaques and progressive impairment of the neuronal integrity. Many experimental drugs have shown preventive effects on the Aβ accumulation. However, these drugs have not passed clinical trials. CiRA Professor Haruhisa Inoue explains there are several reasons.

"Patients are heterogeneous, and Aβ accumulation starts 20 years before the onset," he said.

Inoue believes effective treatments can best be found by studying human specific cells from multiple patients and compounds that have long established safety information.

In its newest study, his group tested over 1,000 drug compounds on neurons made from the iPS cells of Alzheimer's disease patients. The researchers used chemoinformatics to cluster the best candidates into different groups based on the chemical structures. One drug, bromocriptine, was found to lower Aβ accumulation through its ergoline structure by altering Aβ metabolism. Ergoline drugs are common, and the best known is LSD. Bromocriptine, on the other hand, is approved for use against Parkinson's disease.

"Bromocriptine is used in Parkinson's disease because it is an agonist for the dopamine receptor and other receptors. We attribute our findings to changing Aβ metabolism, which is a new mechanism," said Inoue.

Further study considered a combination of the candidates, with the most effective including bromocriptine and two other drugs, topiramate, which is used to treat epilepsy, and cromolyn, which is an anti-inflammatory drug used to treat asthma. Chemoinformatics analysis found that the three drugs clustered differently.

"Each of these drugs have different structures and target different molecules," noted Inoue.

Patients with Alzheimer's disease can be divided into familial (patients who express a gene mutation that is associated with the disease) and sporadic (patients who do not express a causal mutation) groups. The different molecular causes of Alzheimer's disease suggests many experimental drugs will show positive effects on only subsets of Alzheimer's diseases patients. In the study, the initial discovery of the drug combination was made using cells from a familial Alzheimer's disease patient. However, further experiments, in vitro trial, confirmed the same concoction had positive effects on cells made from 13 different familial and sporadic patients

Inoue attributes these findings to the fact that the drug cocktail has multiple targets, which could expand the number of patients who benefit from the treatment. At the same time, he cautions that while encouraging, the study is only a first step.

"Our tests show bromocriptine, cromolyn and topiramate work on isolated neurons, but we do not know if the same effects will be seen inside brains where neurons interact with many other cells," he said.

Paper Details
  • Journal: Cell Reports
  • Title: iPSC-based compound screening and in vitro trials identify a synergistic anti-amyloid β combination for Alzheimer's disease
  • Authors: Takayuki Kondo1,2, Keiko Imamura1,2, Misato Funayama1, Kayoko Tsukita1, Michiyo Miyake1,2, Akira Ohta1, Knut Woltjen1,3, Masato Nakagawa1, Takashi Asada4, Tetsuaki Arai4, Shinobu Kawakatsu5, Yuishin Izumi6, Ryuji Kaji6, Nobuhisa Iwata7,8, Haruhisa Inoue1,2*
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
    2. Drug-Discovery Cellular Basis Development Team, RIKEN BioResource Center, Kyoto, Japan
    3. Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan
    4. Department of Neuropsychiatry, Institute of Clinical Medicine, Tsukuba University, Ibaraki 305-8577, Japan
    5. Department of Neuropsychiatry, Aizu Medical Center, Fukushima Medical University, Fukushima 969-3492, Japan
    6. Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
    7. Department of Gene-based Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
    8. Unit for Dementia Research and Drug Discovery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
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