Abstract：
Alzheimer\'s disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.
摘要：
阿尔茨海默病（AD）是一种具有明显性别偏见的神经退行性疾病。年龄相关的血管改变,AD发病和进展的标志，始终与性二态性有关。这里,我们对AD和正常衰老中血管系统的335,803个单核转录组和667个批量转录组进行了综合荟萃分析,以解决AD中潜在的性别依赖性血管衰老问题.男性AD患者的所有血管细胞类型均表现出激活的缺氧反应和下游信号传导途径，包括血管生成。雌性AD脉管系统的特征在于增加的抗原呈递和减少的血管生成。我们进一步证实，脑血管中的这些性别偏见改变出现，并主要在AD的早期阶段确定。正常血管衰老的性别分层分析显示，血管生成和各种应激反应基因与女性衰老同时下调。相反，随着年龄的增长，男性的缺氧反应稳步增加。对上游驱动转录因子（TF）的研究表明，绝经期间雌激素受体α（ESR1）与缺氧诱导因子之间的通讯改变有助于抑制正常女性血管衰老期间的血管生成。此外,抑制CREB1，一种靶向雌激素的TF，也与女性AD有关。总的来说,我们的研究揭示了女性和男性不同的脑血管特征，揭示了AD精准医学治疗的新靶点。
