Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer's disease.

Abstract Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an “activated” morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II + microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype. The upregulated genes involved in the biological processes (gene ontology terms) included: “immune response to external stimulus” such as Axl , Cd63 , Egr2 , and Lgals3 , “cell motility”, such as Ccl3 , Ccl4 , Cxcr4 , and Sdc3 , “cell differentiation”, and “system development”, such as St14 , Trpm1 , and Spp1 . In human AD tissue with similar Braak stages, expression of phagocytic markers and AD-associated genes, including HLA-DRA , APOE , AXL , TREM2 , and TYROBP , was higher in laser-captured early-onset AD (EOAD) plaques than in late-onset AD plaques. Interestingly, the nonplaque parenchyma of both EOAD and late-onset AD brains, the expression of above-mentioned markers were similarly low. Here, we provide evidence that Aβ plaque-associated microglia are hyperreactive in their immune response and phagocytosis in the transgenic AD mice as well as in EOAD brain tissue. We suggest that Aβ plaque-associated microglia are the primary source of neuroinflammation related to AD pathology.