Figure 3: The role of microglia depends on time and the disease stage. Activated microglia migrate to and engulf amyloid β to clear plaques. Prolonged activation (due to ongoing production of amyloid β) results in enlargement of microglia and altered microglial response. Phagocytosis becomes less efficient, amyloid β-degrading proteolytic enzymes (insulysin, neprilysin, and MMP9) are expressed less, and pro-inflammatory cytokines increase. Consequently, plaque clearance becomes less efficient, while neuroinflammation becomes sustained. This, in turn, leads to some functional and structural changes, some toxic products (reactive oxygen species, etc.), and ultimately degeneration.^[65] TREM2, which is a cell surface receptor, is required for proper microglial functioning. Some TREM2 variants are associated with altered microglial response, decrease in the number and size of plaque-associated microglia, changes in inflammatory cytokines, etc. Time-related changes in activation and expression profile of microglia are now evident. Homeostatic microglia transition as a function of disease progression. Disease-associated microglia cells exhibit enhanced phagocytic activity.^[110] Suppression or insufficiency of disease-associated microglia activity may have implications in neurodegeneration due to Alzheimer's disease, and could be studied for therapeutic potential