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bioRxiv · 10.64898/2025.12.17.694879

BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes

Rodwell-Bullock, J.·Blau, E.·Ganguly, A.·Deaton, C.·Johnson, G. V.
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Abstract

In a healthy brain, astrocytes maintain neuronal homeostasis by removing proteins like tau from the extracellular space, preventing their uptake by neurons. In Alzheimers disease (AD), this function is impaired, contributing to tau accumulation. Many AD risk genes are linked to endocytosis pathways, suggesting their role in AD pathogenesis. Astrocytes can internalize, degrade, and release tau, but the mechanisms remain unclear. BAG3, a multifunctional protein, regulates vacuolar processes and interacts with clathrin-mediated endocytosis (CME) components. However, its role in astrocytic CME and tau processing is not fully understood. We show BAG3 depletion in astrocytes reduces clathrin-AP-2 interaction, inhibits CME-dependent epidermal growth factor receptor internalization, and decreases tau uptake. Live-cell imaging reveals BAG3 depletion impairs CME dynamics, increasing clathrin particle lifetimes. BAG3 depletion also alters endolysosomal compartments, increasing Lamp1+ puncta and tau co-localization. These findings highlight BAG3s role in CME, tau trafficking, and vacuolar processes, suggesting its dysfunction may contribute to AD pathogenesis.

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Rodwell-Bullock, J., Blau, E., Ganguly, A., Deaton, C., Johnson, G. V.. 2025-12-17. BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes. https://doi.org/10.64898/2025.12.17.694879

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