Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease
| Autor: | Yadong Huang, Alice Taubes, Marina Sirota, Tomiko Oskotsky, Misha Zilberter, Seo Yeon Yoon, Maureen E. Balestra, Jessica K De Freitas, Krishna Choudhary, Mesude Bicak, Benjamin S. Glicksberg, Brian P. Grone, Yanxia Hao, William Chang, Bin Chen, Ishan Paranjpe, Alice An, Celine Wang, Phil Nova, Emily Jones, Nuo Chen, Kelly A. Zalocusky, Nicole Koutsodendris, Fayzan Chaudhry, Silvia Pineda, Idit Kosti |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
Apolipoprotein E Aging business.industry media_common.quotation_subject Neuroscience (miscellaneous) Human brain Disease Bioinformatics Drug repositioning medicine.anatomical_structure Drug development medicine Geriatrics and Gerontology Induced pluripotent stem cell business Bumetanide media_common medicine.drug |
| Zdroj: | Nature Aging. 1:932-947 |
| ISSN: | 2662-8465 |
| Popis: | The evident genetic, pathological and clinical heterogeneity of Alzheimer’s disease (AD) poses challenges for traditional drug development. We conducted a computational drug-repurposing screen for drugs to treat apolipoprotein E4 (APOE4)-related AD. We first established APOE genotype-dependent transcriptomic signatures of AD by analyzing publicly available human brain databases. We then queried these signatures against the Connectivity Map database, which contains transcriptomic perturbations of more than 1,300 drugs, to identify those that best reverse APOE genotype-specific AD signatures. Bumetanide was identified as a top drug for APOE4-related AD. Treatment of APOE4-knock-in mice without or with amyloid β (Aβ) accumulation using bumetanide rescued electrophysiological, pathological or cognitive deficits. Single-nucleus RNA sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in APOE4 induced pluripotent stem cell (iPSC)-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 years in two electronic health record databases, suggesting the effectiveness of bumetanide in preventing AD. Through computational drug repurposing, Taubes et al. identified bumetanide as a potential drug for APOE4-related Alzheimer’s disease (AD). The effectiveness of bumetanide was validated in AD mouse models and via real-world health record databases. |
| Databáze: | OpenAIRE |
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