Wu Yiyang, Libby Julia B, Dumitrescu Logan, De Jager Philip L, Menon Vilas, Schneider Julie A, Bennett David A, Hohman Timothy J
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Alzheimers Dement. 2025 Feb;21(2):e14419. doi: 10.1002/alz.14419. Epub 2024 Dec 6.
Using 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.
Negative binomial mixed models were used for differential gene expression and association analysis with AD endophenotypes. VEGF-associated intercellular communication was also profiled.
Higher 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.
Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.
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.
利用来自424名宗教团体研究和拉什记忆与衰老项目（ROS/MAP）参与者的背外侧前额叶皮质的单核转录组，我们研究了10种血管内皮生长因子（VEGF）基因对阿尔茨海默病（AD）内表型的细胞类型特异性影响。
采用负二项混合模型进行差异基因表达分析以及与AD内表型的关联分析。还对VEGF相关的细胞间通讯进行了分析。
小胶质细胞FLT1、内皮细胞FLT4和少突胶质细胞VEGFB水平较高与更高的β淀粉样蛋白（Aβ）负荷相关，而抑制性神经元中较高的VEGFB表达与较低的Aβ负荷相关。星形胶质细胞NRP1水平较高与较低的tau密度相关。小胶质细胞和内皮细胞FLT1水平较高与较差的认知表现相关。与认知正常的对照组相比，临床AD患者的内皮细胞和小胶质细胞FLT1表达上调。最后，与对照组相比，AD细胞的VEGF信号传导显著降低。
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。
FLT1和FLT4的前额叶皮质表达与更差的横断面整体认知功能、纵向认知轨迹以及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由内皮细胞和小胶质细胞驱动。VEGFB表达似乎根据细胞类型对AD中的Aβ负担有相反的影响，突出了其在神经元中的潜在保护作用。
