Functional insight into LOAD-associated microglial response genes

Abstract

Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), neuronal and synaptic loss and inflammation of the central nervous system (CNS). The majority of AD research has been dedicated to the understanding of two major AD hallmarks (i.e. Aβ and NFTs); however, recent genome-wide association studies (GWAS) data indicate neuroinflammation as having a critical role in late-onset AD (LOAD) development, thus unveiling a novel avenue for AD therapeutics. Recent evidence has provided much support to the innate immune system's involvement with AD progression; however, much remains to be uncovered regarding the role of glial cells, specifically microglia, in AD. Moreover, numerous variants in immune and/or microglia-related genes have been identified in whole-genome sequencing and GWAS analyses, including such genes as TREM2, CD33, APOE, API1, MS4A, ABCA7, BIN1, CLU, CR1, INPP5D, PICALM and PLCG2. In this review, we aim to provide an insight into the function of the major LOAD-associated microglia response genes.

Keywords: Alzheimer's; LOAD; TREM2; microglia.

Figure 1.

AD risk variants and associated effect on altered microglial function in the presence of AD pathology. CSF, cerebrospinal fluid; DAM, disease-associated microglia; SNP, single nucleotide polymorphism.

Figure 2.

Putative functions of LOAD-associated genes in microglial cells. Microglial response to pathogenic targets such as Aβ and tau begins with initial recognition via receptors such as TREM2. TREM2 signals through DAP12 to affect intracellular calcium signalling and DAM gene expression, which leads to functional outputs such as inflammatory signalling and phagocytic uptake of targets. CD33 detects sialylated targets (blue squares) and is an inhibitor of phagocytosis and opposes TREM2 signalling. sTREM2 is cleaved from full-length TREM2 and is also involved in NF-kB signalling and inflammatory response. MS4A is a transmembrane protein that is known to influence calcium signalling and modulate TREM2 processing into sTREM2. ABCA7 is a transporter protein and there is evidence that it affects the endolysosomal function and metabolism of lipids, which can affect APOE. APOE is involved in cholesterol metabolism and is found to associate with Aβ plaques, affecting their interaction with TREM2. (Created with BioRender.com.)