INTRODUCTIONUsing a single‐nucleus transcriptome derived from the dorsolateral prefrontal cortex of 424 Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP) participants, we investigated the cell type–specific effect of ten vascular endothelial growth factor (VEGF) genes on Alzheimer's disease (AD) endophenotypes.METHODSNegative binomial mixed models were used for differential gene expression and association analysis with AD endophenotypes. VEGF‐associated intercellular communication was also profiled.RESULTSHigher microglia FLT1, endothelial FLT4, and oligodendrocyte VEGFB are associated with greater amyloid beta (Aβ) load, whereas higher VEGFB expression in inhibitory neurons is associated with lower Aβ load. Higher astrocyte NRP1 is associated with lower tau density. Higher microglia and endothelial FLT1 are associated with worse cognition performance. Endothelial and microglial FLT1 expression was upregulated in clinical AD patients compared to cognitively normal controls. Finally, AD cells showed a significant reduction in VEGF signaling compared to controls.DISCUSSIONOur results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.Highlights The prefrontal cortical expression of FLT1 and FLT4 was associated with worse cross‐sectional global cognitive function, longitudinal cognitive trajectories, and more Alzheimer's disease (AD) neuropathology. The associations between FLT1 or FLT4 and AD endophenotypes appear to be driven by endothelial and microglial cells. VEGFB expression seems to have opposing effects on the Aβ burden in AD depending on cell types, highlighting its potential protective role in neurons.

中文翻译：

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10 个 VEGF 家族基因与单细胞分辨率下阿尔茨海默病内表型的相关性


引言利用源自 424 个宗教秩序研究和 Rush Memory and Aging Project （ROS/MAP） 参与者的背外侧前额叶皮层的单核转录组，我们研究了 10 个血管内皮生长因子 （VEGF） 基因对阿尔茨海默病 （AD） 内表型的细胞类型特异性影响。方法采用基因二项式混合模型进行差异基因表达和与 AD 内表型的关联分析。还分析了 VEGF 相关的细胞间通讯。结果高等小胶质细胞 FLT1 、内皮细胞 FLT4 和少突胶质细胞 VEGFB 与较高的淀粉样蛋白 β （Aβ） 载量相关，而抑制性神经元中较高的 VEGFB 表达与较低的 Aβ 载量相关。较高的星形胶质细胞 NRP1 与较低的 tau 密度相关。较高的小胶质细胞和内皮 FLT1 与较差的认知表现相关。与认知正常的对照相比，临床 AD 患者的内皮和小胶质细胞 FLT1 表达上调。最后，与对照组相比，AD 细胞显示 VEGF 信号转导显着减少。讨论我们的结果突出了 AD 期间内皮细胞和小胶质细胞中 VEGF 受体表达的关键变化，以及 VEGFB 在神经元中的潜在保护作用。亮点 FLT1 和 FLT4 的前额叶皮质表达与较差的横断面整体认知功能、纵向认知轨迹和更多的阿尔茨海默病 （AD） 神经病理学相关。FLT1 或 FLT4 与 AD 内表型之间的关联似乎是由内皮细胞和小胶质细胞驱动的。根据细胞类型，VEGFB 表达似乎对 AD 中的 Aβ 负荷具有相反的影响，突出了它在神经元中的潜在保护作用。