Amyloid-β clearance: an astrocytic perspective

Alzheimer’s disease (AD) represents a major global public health challenge in the 21st century, recognized as the neurodegenerative disorder with the highest mortality rate and socioeconomic burden. The core pathological feature of AD is an imbalance in A β production and clearance, leading to conformational changes and pathological aggregation of A β peptides. This imbalance triggers neurodegenerative cascades 20–30 years before clinical symptoms appear. Therapeutic approaches targeting A β production, including β -secretase and γ -secretase inhibitors, have thus far shown limited clinical benefit in late-stage trials and have been further constrained by safety and tolerability concerns. As a result, early interventions aimed at enhancing A β clearance have attracted increasing attention. While microglia-mediated phagocytosis of A β has been extensively studied, the multifaceted roles of astrocytes in this process remain underexplored. This review synthesizes recent findings to elucidate the molecular mechanisms of astrocyte-mediated A β clearance, focusing on endocytic uptake and intracellular degradation, maintenance of the blood–brain barrier, and aquaporin-4 (AQP4)-dependent glymphatic drainage. Additionally, this review dissects key regulatory nodes, including the dynamic modulation of A β clearance capacity through astrocyte phenotypic transitions and functional decline associated with pathology. These insights offer a theoretical foundation and translational perspective for the development of astrocyte-targeted interventions in early-stage AD.