GFAP upregulation by astrocytes attenuates tau neurofibrillary tangle pathology in a mouse model of tauopathy

Abstract Background The upregulation of the intermediate filament glial fibrillary acidic protein (GFAP) by reactive astrocytes has been traditionally assigned structural functions such as the shaping of astrocyte morphology and the formation of the glial scar. However, in vitro studies have also implicated GFAP in chaperone-mediated autophagy and endolysosomal trafficking. Here we hypothesized a role of GFAP in proteostasis in neurodegenerative proteinopathies. Specifically, we tested whether GFAP upregulation by reactive astrocytes helps control phospho-tau (pTau) neurofibrillary tangle burden in vivo. Methods We investigated the interactome of GFAP in human control and AD brains via co-immunoprecipitation (co-IP) followed by mass spectrometry. We also overexpressed GFAP in the astrocytes of THY-Tau22 mice using a viral transfer approach and characterized downstream effects on astrocyte phenotype, pTau burden, and neurodegenerative measures by combining immunohistochemistry, biochemistry, RNA-sequencing, and co-IP/mass spectrometry. Results We show that the interactome of GFAP immunoprecipitated from human control and AD brains is unexpectedly enriched in proteostasis effectors. Overexpressing GFAP in astrocytes of THY-Tau22 mice reduced hippocampal pTau neurofibrillary tangle burden, increased presynaptic marker levels, and modulated neuronal c-Fos 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-IP/mass spectrometry revealed an extensive network of proteostasis-related interactors, including components of endocytosis/macropinocytosis, lysosomal autophagy, heat shock protein response, and the ubiquitin-proteasome system. Conclusions These findings challenge the conventional view of GFAP as a mere scaffold protein of the astrocyte cytoskeleton and suggest a novel role of GFAP in proteostasis with potential neuroprotective effects.