Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease.
Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease.
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实验和现实世界证据支持布美他尼的计算再利用，用于治疗 APOE4 相关的阿尔茨海默病。
DOI：
10.1038/s43587-021-00122-7
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Huang, Yadong
中科院分区：
文献类型：
--
作者：
Taubes, Alice;Nova, Phil;Zalocusky, Kelly A.;Kosti, Idit;Bicak, Mesude;Zilberter, Misha Y.;Hao, Yanxia;Yoon, Seo Yeon;Oskotsky, Tomiko;Pineda, Silvia;Chen, Bin;Jones, Emily A. Aery;Choudhary, Krishna;Grone, Brian;Balestra, Maureen E.;Chaudhry, Fayzan;Paranjpe, Ishan;De Freitas, Jessica;Koutsodendris, Nicole;Chen, Nuo;Wang, Celine;Chang, William;An, Alice;Glicksberg, Benjamin S.;Sirota, Marina;Huang, Yadong
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 (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation 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-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.
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DOI：
10.1523/jneurosci.0033-12.2012
发表时间：
2012-04-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bien-Ly N;Gillespie AK;Walker D;Yoon SY;Huang Y
通讯作者：
Huang Y
影响因子：
4.8
作者：
Goubert, Emmanuelle;Altvater, Marc;Pellegrino, Christophe
通讯作者：
Pellegrino, Christophe
影响因子：
4.7
作者：
Falcón E;McClung CA
通讯作者：
McClung CA
影响因子：
64.5
作者：
Huang Y;Mucke L
通讯作者：
Mucke L
影响因子：
6
作者：
Gharaylou, Zeinab;Tafakhori, Abbas;Hadjighassem, Mahmoudreza
通讯作者：
Hadjighassem, Mahmoudreza