Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress

Abstract

Microglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally linked to amyloid beta (Aβ) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were also attributed beneficial roles, notably in the phagocytic elimination of Aβ. In this review, we discuss the interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially focusing on chronic stress as an environmental risk factor modulating their function, and present recently-described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed under both chronic stress and AD pathology may provide novel opportunities for the development of better-targeted therapeutic interventions.

Keywords: ABCA7, ATP-binding cassette transporter A7; AD, Alzheimer's disease; APOE, Apolipoprotein E; APP, amyloid precursor protein; Alzheimer's disease; Aβ, Amyloid beta; BDNF, brain derived neurotrophic factor; CD11b, cluster of differentiation molecule 11B; CD33, cluster of differentiation 33; CNS, central nervous system; CR, complement receptor; CRF, corticotropin releasing factor; DAM, disease associated microglia; DAP12, DNAX-activation protein 12; Dark microglia; FAD, Familial Alzheimer's disease; FCRLS, Fc receptor-like S scavenger receptor; GR, glucocorticoid receptor; HPA axis, hypothalamic pituitary adrenocortical axis; IBA1, ionized calcium-binding adapter molecule 1; IL, interleukin; LTP, long-term potentiation; MGnD, microglia with a neurodegenerative phenotype; MR, mineralocorticoid receptor; Microglia; Microglial phenotypes; NADPH, nicotinamide adenine dinucleotide phosphate; NFT, neurofibrillary tangles; Neurodegeneration; Neuroinflammation; PS, presenilin; ROS, reactive oxygen species; Stress; Synaptic remodeling; TGFβ, transforming growth factor β; TLR, Toll-like receptors; TMEM119, transmembrane protein 119; TNFα, tumor necrosis factor-α; TREM2, triggering receptor expressed in myeloid cells 2; TYROBP, TYRO protein tyrosine kinase binding protein; mPFC, medial prefrontal cortex.

Fig. 1

Overview of the AD pathology mouse models mentioned in the review. Data compiled from Alzforum Alzheimer's disease research model database (https://www.alzforum.org/research-models/alzheimers-disease).

Fig. 2

Overview of microglial functions in response to stress and AD pathology.