GFAP Upregulation by Astrocytes Attenuates Tau Neurofibrillary Tangle Pathology in a Mouse Model of Tauopathy

Here we reveal that the human GFAP interactome is enriched in chaperones and endo-lysosomal proteins, suggesting a functional link to proteostasis. We show that overexpressing GFAP in astrocytes of a tauopathy mouse model reduced hippocampal neurofibrillary tangle burden, increased synaptophysin levels, and modulated neuronal cFos expression, with more pronounced effects in female mice.

Mechanistically, transcriptomic analysis revealed an induction of genes involved in extracellular matrix and small GTPases mediating cytoskeleton dynamics, whereas co-immunoprecipitation/mass spectrometry revealed an extensive network of proteostasis-related interactors, including components of endocytosis, lysosomal autophagy, heat shock response, and the ubiquitin-proteasome system. These findings challenge the conventional view of GFAP as a mere scaffold protein of the astrocyte cytoskeleton and highlight a novel neuroprotective role of GFAP in the clearance of misfolded proteins.