Microglia and its Genetics in Alzheimer's Disease

Abstract

: Alzheimer’s Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid- beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in terms of both pathogenesis and progression. As the main innate immune cell type in the central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions, including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complex etiology of AD and provide new insight into the unmet need for effective treatment.

Bibliometric analysis of global research on the role of apolipoprotein E in Alzheimer's disease

“…A prominent feature of AD is the proliferation and activation of microglia concentrated around amyloid plaques. A recent study reported that microglia in the brain can highly and selectively express many risk genes for AD [ 45 ]. Krasemann et al [ 25 ] identified the triggering receptor expressed on myeloid cells 2 (TREM2)-APOE pathway as the major regulator of microglial functional phenotype, which switches the cellular state from homeostasis to the neurodegenerative state.…”

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

“…Among them are the amyloid-and the interferon-response microglia (ARM and IRM, respectively) [226]. ARM is exclusively associated with amyloid deposits (insoluble Aβ plaques), and thus also known as PAM (plaque-associated microglia) [217,227]. ARM is characterized by its hyperreactivity in the immune response, overexpressing genes related to neuroinflammatory process (Cst7 and Clec7a), tissue repair (Dkk2, Gpnmb and Spp1) and the activation of the major histocompatibility complex (MHC) class II (Cd74, Ctsd and Ctsb) [226].…”

Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice

“…2j, k). Furthermore, we performed transcriptional analysis of a panel of genes 35 that are highly expressed in AD-associated microglia 36 . The results showed the decreased expression of these genes, such as inflammatory cytokines including Tnfa and Il1a , complement factors including C1q, C3 and C4a , and IFN-stimulated genes such as Ifit1 and Oas1 , in hippocampal tissues of Cgas −/− ;5×FAD mice relative to their Cgas +/+ ;5×FAD littermates (Fig.…”