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

ABSTRACT: The upregulation of the intermediate filament glial fibrillary acidic protein (GFAP) by reactive astrocytes in response to injury has been traditionally assigned a structural function. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE300587 | GEO | 2026/08/23

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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

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