RT Journal Article
T1 Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer’s disease
A1 Alice Taubes, Alice
A1 Nova, Phil
A1 Zalocusky, Kelly A.
A1 Kosti, Idit
A1 Bicak, Mesude
A1 Zilberter, Misha Y.
A1 Hao, Yanxia
A1 Yoon, Seo Yeon
A1 Oskotsky, Tomiko
A1 Pineda Sanjuan, Silvia
A1 Bin Chen, Emily A.
A1 Jones, Aery
A1 Choudhary, Krishna
A1 Grone, Brian
A1 Balestra, Maureen E.
A1 Chaudhry, Fayzan
A1 Paranjpe, Ishan
A1 De Freitas, Jessica
A1 Koutsodendris, Nicole
A1 Chen, Nuo
A1 Wang, Celine
A1 William Chang, William
A1 An, Alice
A1 Glicksberg, Benjamin S.
A1 Sirota, Marina
A1 Huang, Yadong
A2 Thuault, Sebastien
AB 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.
PB Nature Publishing Group
SN 2662-8465
YR 2021
FD 2021-10-11
LK https://hdl.handle.net/20.500.14352/96873
UL https://hdl.handle.net/20.500.14352/96873
LA eng
NO Taubes, A., Nova, P., Zalocusky, K. A., Kosti, I., Bicak, M., Zilberter, M. Y., Hao, Y., Yoon, S. Y., Oskotsky, T., Pineda, S., Chen, B., Jones, E. A. A., Choudhary, K., Grone, B., Balestra, M. E., Chaudhry, F., Paranjpe, I., De Freitas, J., Koutsodendris, N., … Huang, Y. (2021). Experimental and real-world evidence supporting the computational repurposing of bumetanide for apoe4-related alzheimer’s disease. Nature Aging, 1(10), 932–947.
NO National Institutes of Health
DS Docta Complutense
RD 6 abr 2025