Unraveling the complex role of microglia in Alzheimer's disease: amyloid β metabolism and plaque formation

BackgroundAlzheimer's disease (AD) is characterized by amyloid beta (A beta) accumulation in the brain. Recent genome-wide association studies have identified numerous AD risk genes highly expressed in microglia, highlighting their potential role in AD pathogenesis. Although microglia possess phagocytic capacity and have been implicated in A beta clearance, accumulating evidence suggests their contribution to AD pathogenesis is more complex than initially anticipated.Main bodyThis review synthesizes current knowledge on microglial A beta metabolism in AD, reconciling conflicting data from various studies. We examine evidence supporting the role of microglia in A beta clearance, including studies on AD risk genes like TREM2 and their impact on microglial phagocytosis. Conversely, we explore findings that challenge this view, such as microglial depletion experiments resulting in unchanged or decreased A beta accumulation. We propose that the contribution of microglia to A beta metabolism is context-dependent, varying with disease progression, genetic background, and experimental conditions. Notably, microglia may promote parenchymal amyloid accumulation in early disease stages, while this accumulation-promoting effect may diminish in later stages. We discuss potential mechanisms for this paradoxical effect, including intracellular A beta aggregation and release of pro-aggregation factors. Additionally, we explore the interplay between microglia-mediated A beta metabolism and other clearance pathways, such as the glymphatic system, highlighting a potential compensatory relationship between parenchymal amyloid deposition and cerebral amyloid angiopathy.ConclusionOur review underscores the complex and dynamic role of microglia in AD pathogenesis. Understanding the stage-specific functions of microglia in A beta metabolism is crucial for developing targeted interventions. Future research should focus on elucidating the mechanisms of microglial functional changes throughout disease progression and determining the pathological significance of these changes. Exploring potential therapeutic strategies that selectively enhance beneficial microglial functions while mitigating their detrimental effects remains an important goal.