Microglia are innate immune cells resident in the brain, somewhat analogous to macrophages elsewhere in the body. Like macrophages, microglia exhibit a diverse set of states, and can shift from one state to another in response to circumstances. At the high level, much of the literature focuses on the inflammatory M1 state, capable of hunting and destroying pathogens and errant cells, versus the anti-inflammatory M2 state, focused on regeneration and tissue maintenance. But, as the authors of today's open access paper point out, this is an oversimplification of a much more complex continuum of states, some of which don't fit well into the M1 or M2 buckets.
So while it is possible to argue that microglia are important in neurodegenerative conditions in large part because too many of them become inflammatory and dysfunctional in response to the aged tissue environment in the brain, the fine details do matter. Some microglia are more harmful than others, some are more helpful than others, and attempts to broadly adjust the state of microglia may be less helpful than hoped. The suspicion is that more of the panoply of states must be understood in greater detail, and targeted distinctly.
Despite extensive research, the role of microglia in Alzheimer's disease (AD) remains complex and dual. The aim of this review is to summarize the most recent advances in research regarding the dual role of microglia in AD concerning both immunomodulation and pathological progression by considering mechanisms of activation of microglia, effects on amyloid-β (Aβ) clearance, tau pathology, and impacts due to genetic variations on microglial functions.
The functional state of microglia, the principal immune cells of the central nervous system (CNS), is far more complex than the traditional M1 and M2 phenotype polarization. Current studies have shown that the state of microglia in AD can comprise a wide variety of different phenotypes that play different roles in different stages of the disease and microenvironments. Aside from the classic M1 and M2 phenotypes, studies have characterized conditions such as disease-associated microglia (DAM) and reactive microglia (RAM) that have specific functional and molecular profiles in AD pathology.
M1 microglia are activated when stimulated by proinflammatory factors such as interferon-γ and lipopolysaccharide, and release proinflammatory factors such as TNF-α, IL-6, IL-1β, and inducible nitric oxide synthase. Excessive secretion of these factors aggravates neuroinflammatory reaction and toxic injury of neurons, and promotes the accumulation of Aβ and the hyperphosphorylation of tau protein. In contrast, M2 microglia are activated by anti-inflammatory factors such as interleukin-4 (IL-4) and interleukin-13 (IL-13), and secrete anti-inflammatory and neurotrophic factors such as interleukin-10 (IL-10), transforming growth factor β (TGF-β), BDNF, and glial-derived neurotrophic factor (GDNF).
Additionally, disease-associated microglia (DAM) have distinct initial AD gene expression patterns and are found surrounding Aβ plaques and clear Aβ as well as modulate tau pathology. TREM2 variants were significantly associated with AD risk increase and that its physiological function is to allow for DAM formation and thus increased Aβ clearance. Pathology of tau also significantly increases with deficient TREM2 function or microglial deficiency, pointing toward an essential role of DAM in the prevention of tau spreading. The phenotypes of AD in microglia are beyond the simple M1 and M2 phenotypes but more evolved phenotypes such as DAM. Each state has its own corresponding functions to perform in the different stages of the disease and microenvironment, and in the future, further molecular mechanisms and functional difference among the states would have to be investigated by studies to un-scramble the multi-functional role of microglia in AD.
View the full article at FightAging
