Fig. 2

Microglial features in Alzheimer’s disease (AD). a AD is pathologically characterized by extracellular beta-amyloid (Aβ) aggregates, intracellular tau neurofibrillary tangles (NFT) and neuronal cell death. b In the setting of AD, microglia act as the initial responders to brain damage and respond to various pathological hallmarks, including Aβ oligomer, tau and myelin debris, adopting DAM and IFN-responsive microglia features via pathways that are in part TREM2 or APOE-dependent. Both DAM and IFN-R microglia are characterized by downregulation of homeostatic genes (such as P2ry12). DAM upregulate various genes, such as Clec7a. IFN-R microglia feature a list of up-regulated genes, including Irf7 and Stat1. Transcriptional factors, such as Bhlhe40, Tfec and Atf3, are commonly induced in the reactive microglia through “TREM2-APOE” signaling. c In Aβ-bearing pathology, TREM2 and APOE collaboratively serve as a barrier to limit Aβ-induced neuronal toxicity by inducing microglial clustering. Lack of TREM2 or APOE results in a defect of DAM, and abundant Aβ42 and dystrophic neurites around filamentous plaques. d In tauopathy, TREM2 or APOE deficiency limits microgliosis and restrain neuronal loss in late-stage disease. DAM, disease-associated microglia; IFN-R, IFN-I-response