在正常衰老和阿尔茨海默病中，等位基因对神经胶质转录组的影响。
Effect of alleles on the glial transcriptome in normal aging and Alzheimer's disease.
机构信息
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Massachusetts Alzheimer's Disease Research Center, Charlestown, MA, USA.
出版信息
Nat Aging. 2021 Oct;1(10):919-931. doi: 10.1038/s43587-021-00123-6. Epub 2021 Oct 11.
Abstract
The roles of ε4 and ε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in ε4 and downregulated in ε2 carriers relative to ε3 homozygotes. This microglia- cluster is enriched in phagocytosis-including and -and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human -linked expression patterns. Thus, the ε4 allele might prime microglia towards a phagocytic and proinflammatory state through an axis in normal aging as well as in Alzheimer's disease.
摘要
ε4 和 ε2（阿尔茨海默病最强的遗传风险和保护因素）在神经胶质反应中的作用仍不清楚。我们通过研究来自没有神经纤维缠结淀粉样斑块的老年对照大脑的神经胶质转录组，测试了等位基因通过差异影响神经胶质反应的假设。我们鉴定了一组小胶质细胞基因，这些基因在 ε4 携带者中上调，而在 ε2 携带者中下调，相对于 ε3 纯合子。这个小胶质细胞簇富含吞噬作用，包括和，以及促炎基因，在有频繁神经纤维缠结的大脑中也可以检测到。接下来，我们在接受急性（脂多糖挑战）和慢性（脑β淀粉样蛋白病）损伤的基因敲入小鼠中测试了这些发现，发现这些小鼠部分再现了人类相关的表达模式。因此，ε4 等位基因可能通过在正常衰老以及阿尔茨海默病中起作用的轴使小胶质细胞向吞噬和促炎状态倾斜。
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