MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia
- 1Washington University in St. Louis School of Medicine
Abstract
Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.
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BibTeX
@misc{schache2026mapt,
title = {{MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia}},
author = {K. J. Schache and R. Zhang and A. E. Street and E. Starr and J. A. Marsh and D. J. Kast and S. Temple and A. K. Iyer and C. M. Karch},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.27.747662},
url = {https://www.biorxiv.org/content/10.64898/2026.08.27.747662v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia
AU - K. J. Schache
AU - R. Zhang
AU - A. E. Street
AU - E. Starr
AU - J. A. Marsh
AU - D. J. Kast
AU - S. Temple
AU - A. K. Iyer
AU - C. M. Karch
PY - 2026
DA - 2026/08/27
PB - bioRxiv
DO - 10.64898/2026.08.27.747662
UR - https://www.biorxiv.org/content/10.64898/2026.08.27.747662v1
AB - Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.
ER -