Microglia and microglial-based receptors in the pathogenesis and treatment of Alzheimer’s disease

• Published in: International immunopharmacology Vol. 110; p. 109070
• Main Authors: Wang, Zhiyu, Weaver, Donald F.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2022
• Subjects: Alzheimer’s disease; Cytokine; Innate immunity; Microglia; Neuroinflammation; β-amyloid; TREM; BBB; M-CSF; RNA; Chi3l3; MHC; CXCL13; IL-1R; Aβ; NF-κB; PRR; FcR; SDF; GM-CSF; iNOS; A2AR; β-amyloid; AD; CR1; IL; Alzheimer’s disease; Arg1; Cytokine; MMP3; IGF-1; GlcH; NGF; G-CSF; MAC; Microglia; MIP; ROS; LTA; FcγR; ERK; NO; oAβ; COX-2; Innate immunity; CNS; FPR; LPS; NLR; CSF; NLRP3; TGF-β; TLR; SR; CD; BDNF; VEGF; Neuroinflammation; AGEs; AKT; ox-LDL; RAGE; MERTK; ECM; PAMP; STAT; TNF-α; fAβ; TIR; ATP; DAMP
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2022.109070

[Display omitted] •Alzheimer’s disease is characterized by neurotoxic immuno-inflammation and cytotoxic protein aggregation, culminating in concomitant, parallel, interconnected immunopathic and proteopathic pathogeneses.•Microglia recognize different forms of misfolded proteins and are activated to initiate immune responses, facilitating tissue repair.•Dysregulated microglial activation induces inflammation/immunotoxicity and neurotoxicity.•Activated microglia afford a multiplicity of biochemical and histological pathways, many of which offer druggable targets.•Manipulating microglia metabolism is a potential therapeutic approach to neuroinflammation. Alzheimer’s disease (AD) manifests as progressive deterioration in multiple cognitive and information processing domains, including memory and executive functions. Although AD’s cause and cure remain elusive, increasing evidence supports a key role for microglial cells in AD pathogenesis via diverse mechanisms. β-Amyloid (Aβ) and tau triggered proteopathic and immunopathic processes are key contributors to AD pathology. These proteins aggregate into oligomers and fibrils, which eventually deposit in the central nervous system (CNS) as plaques and tangles. Aβ and tau are directly synaptotoxic and neurotoxic, but also concomitantly induce neuroinflammation. As a central player in CNS immunity, microglia recognize different forms of misfolded proteins and initiate subsequent immune responses, mediating neuroinflammation and neuron-glia crosstalk. Microglia phagocytose debris and release cytokines to maintain brain homeostasis and synaptic integrity. However, microglia also exhibit harmful effects when subject to prolonged activation. This review describes the role of microglia in the proteopathic-immunopathic pathogeneses of AD. We summarize the microglial receptors involved in Aβ recognition, and the role played by this interaction in explaining the interplay between Aβ accumulation and AD progression through microglia-mediated neuroinflammation. Based on the dual proteopathic and immunopathic roles of microglia, we also review putative drug candidates targeting microglial receptors.