GFAP Upregulation by Astrocytes May Attenuate Phospho‐Tau Levels in a Tauopathy Mouse Model

Abstract Background Astrocytes react to amyloid‐β plaques and phospho‐tau (pTau) neurofibrillary tangles in the Alzheimer’s disease brain but their net effect on these Alzheimer’s neuropathological hallmarks remains controversial. A well‐known feature of these so‐called “reactive astrocytes” is the upregulation of the intermediate filament glial fibrillary acidic protein (GFAP), which is thought to be necessary for astrocyte process motility and glial scar formation. Here we asked whether this cytoskeletal remodeling helps reactive astrocytes control the burden of pTau species and/or protect synapses and neurons. Method We overexpressed human GFAP isoform 1 specifically in astrocytes of 4‐month‐old, sex‐balanced, THY‐Tau22 mice (Thy1.2‐ MAPT G272V/P301S 1N4R, GFAP mice, n = 11)—when neurofibrillary tangles start to appear in the hippocampal CA1 subfield—using a viral transfer strategy with single retro‐orbital intravenous injection of AAV‐PHP.B (2.5×10 11 vg) and the gfaABC 1 D promoter. We euthanized the mice at 11 months of age (i.e., prior to the tauopathy plateau) and performed immunohistochemical and/or biochemical analysis of astrocyte, tau, and synaptic markers. Negative control groups consisted of THY‐Tau22 littermates injected with either phosphate‐buffered saline (PBS mice, n = 9) or an AAV‐PHP.B vector encoding the enhanced green fluorescent protein (EGFP mice, n = 10). Results Immunohistochemistry confirmed the astrocyte‐specific expression of human GFAP with an apparent integration in their intermediate filament network. We observed statistically significant reductions or marginally significant trends toward decrease in hippocampal SDS‐soluble levels AT8/pTau Ser202/Thr205 and AT8‐immunoreactive area fraction, and a shift of AT180/pTau Thr231 from SDS‐soluble (decreased) to TBS‐soluble (increased) hippocampal protein fractions, in GFAP vs . EGFP and/or PBS mice, but no changes in soluble or insoluble total tau or AT270/pTau Thr181 across groups. In the cortex, we detected no changes in soluble or insoluble total tau, AT8/pTau Ser202/Thr205 , or AT270/pTau Thr181 levels, nor in AT8‐immunoreactive area. Lastly, we found no significant differences across groups in brain weight, cortical or hippocampal areas, nor in the cortical levels of synaptophysin, Psd95, or the glutamate transporters Eaat1/Glast‐1 and Eaat2/Glt‐1. Conclusion Our findings indicate that GFAP upregulation by astrocytes—a classic feature of reactive astrogliosis—may attenuate neuronal pTau burden in a tauopathy mouse model. Ongoing work will further elucidate whether this aspect of reactive astrocytes impacts pTau‐induced neurodegeneration.