GSE182764
Computational Repurposing of Bumetanide for Preventing or Treating Alzheimer's Disease [AT01_J20_apoEKI_Bumex_snRNA-seq]
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 Ab 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 EHR databases, suggesting effectiveness of bumetanide in preventing AD. Overall design: Single Nucleus Seq of the hippocampus of J20/apoE4-KI 10 month old mice treated with 0.2 mg/kg bumetanide or vehicle control