Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

Abstract

Brain aging is central to late-onset Alzheimer's disease (LOAD), although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.

Keywords: Alzheimer's disease; amyloid-beta peptide; microglia; neurodegeneration; neuroinflammation; proteopathy; tau protein.

Figure 1

Described are five steps of apoptotic cell clearance via phagocytes. Trace chemicals and molecules associated with cell necrosis and apoptosis stimulate the chemotaxis of phagocytes up their concentration gradient to the source. From there, the phagocyte engulfs the apoptotic debris and begins degradation. Eventually, it will release anti-inflammatory and reparative signals such as TGF-β, IL-10, and PGE2. In neurodegenerative diseases of protein aggregation, protein seed aggregates are packaged into exosomes where they can be shuttled to different regions of the CNS.

Figure 2

Three common microglia phenotypes are described. Homeostatic microglia are found in the adult brain under non-infectious, non-diseased, and non-aged conditions, exhibiting robust expression of homeostatic microglial markers: Tmem119, P2ry12, Tgfbr1, and transcription factor Sall1. During normal aging, homeostatic markers gradually decline, resulting in reduced functional aspects, including proliferation, phagocytosis, ramification, and cytokine secretion. Finally, there is a distinct microglia phenotype that is associated with neurodegeneration that possesses a more exacerbated dystrophic phenotype, but is specifically associated with plaques and dystrophic neurites that cause neurodegeneration.