TREM2 Associated with Inability of Aged Microglia to Clear Amyloid-β in the Brain

TREM2 has become a gene of interest in Alzheimer's research, particularly now that a greater focus is given to chronic inflammation, and other aspects of immune aging, in the development and progression of this and other neurodegenerative conditions. TREM2 is a receptor that mediates the ability of microglia, innate immune cells of the brain, to take up and clear amyloid-β aggregates from the brain. Targeting TREM2 with antibodies appears to improve the ability of microglia to perform this task. Absent this sort of intervention, however, microglia in aged individuals both lose TREM2 expression and become less capable of amyloid-β clearance.

Age-associated microglial dysfunction contributes to the accumulation of amyloid-β (Aβ) plaques in Alzheimer's disease. Although several studies have shown age-related declines in the phagocytic capacity of myeloid cells, relatively few have examined phagocytosis of normally aged microglia. Furthermore, much of the existing data on aging microglial function have been generated in accelerated genetic models of Alzheimer's disease. Here we found that naturally aged microglia phagocytosed less Aβ over time. To gain a better understanding of such dysfunction, we assessed differences in gene expression between young and old microglia that either did or did not phagocytose Aβ.

Young microglia had both phagocytic and neuronal maintenance signatures indicative of normal microglial responses, whereas, old microglia, regardless of phagocytic status, exhibit signs of broad dysfunction reflective of underlying neurologic disease states. We also found downregulation of many phagocytic receptors on old microglia, including TREM2, an Aβ phagocytic receptor. TREM2 protein expression was diminished in old microglia and loss of TREM2+ microglia was correlated with impaired Aβ uptake, suggesting a mechanism for phagocytic dysfunction in old microglia. Combined, our work reveals that normally aged microglia have broad changes in gene expression, including defects in Aβ phagocytosis that likely underlies the progression to neurologic disease.


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