摘要
阿爾茨海默病 (AD) 遺傳、病理和臨床異質性證據對傳統藥物開發提出了挑戰。我們對治療載脂蛋白 E4 (APOE4) 相關 AD 的藥物進行了計算藥物再利用篩選。我們首先通過分析公開可用的人腦數據庫建立了 AD 的 APOE 基因型依賴性轉錄組特征。然後，我們根據 Connectivity Map 數據庫查詢這些特征，該數據庫包含 1,300 多種藥物的轉錄組擾動，以確定那些最能逆轉 APOE 基因型特異性 AD 特征的藥物。布美他尼被選定為 APOE4 相關 AD 的最佳藥物。使用布美他尼治療無或有澱粉樣蛋白 β (Aβ) 積累的 APOE4 敲入小鼠可挽救電生理、病理或認知缺陷。單細胞RNA 測序揭示了這些小鼠特定細胞類型中 AD 特征的轉錄組學逆轉，這一發現在 APOE4 誘導的多能幹細胞 (iPSC) 衍生神經元中得到證實。在人類中，在兩個電子健康記錄數據庫中，布美他尼服用與 65 歲以上個體的 AD 患病率顯著降低有關，提示布美他尼在預防 AD 中的有效性
Abstract
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.
