Astrocyte-mediated clearance of protein aggregates: defining properties and regulators

Astrocytes play a critical role in clearing extracellular protein aggregates, yet the mechanisms underlying this process remain unclear. Herein, we investigated how primary murine and human astrocytes internalize α-synuclein and tau aggregates. Proteomic analysis of endo-lysosomal compartments identified heparan sulfate proteoglycans (HSPGs) and integrins as key mediators of aggregate recognition and uptake. Functional assays confirmed HSPG-dependent internalization and highlighted the contribution of mechanosensitive proteins, such as Zyxin, in coordinating cytoskeletal dynamics during uptake. Transcriptomic profiling of striatal astrocytes in vivo following α-synuclein exposure revealed early shifts in metabolic and signaling pathways, suggesting that astrocytes respond to aggregates before neurodegeneration occurs. Additionally, 3D astrocyte cultures maintained in vitro preserved in vivo-like morphology and functional capacity, allowing exploration of how biomechanical cues influence internalization. Together, these findings demonstrate that astrocytic clearance of pathological proteins is governed by a coordinated network of biochemical and biomechanical signals, and that transcriptional changes accompany early responses to protein aggregates. This work provides mechanistic insights and an experimental framework for studying astrocyte mediated protein clearance in health and disease.