Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Introduction In Alzheimer’s disease clinical research, glial fibrillary acidic protein (GFAP) released into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-β (Aβ) or tau pathology. The molecular underpinnings behind this specificity are unexplored. Here we investigated biomarker and transcriptomic associations of GFAP-positive astrocytes with Aβ and tau pathologies in humans and mouse models. Methods We studied 90 individuals with plasma GFAP, Aβ- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aβ (PS2APP) or tau (P301S) pathologies was applied to explore differentially expressed genes (DEGs), Gene Ontology processes, and protein-protein interaction networks associated with each phenotype. Results In humans, we found that plasma GFAP associates with Aβ but not tau pathology. Unveiling the unique nature of GFAP-positive astrocytic responses to Aβ or tau pathology, mouse transcriptomics showed scarce overlap of DEGs between the Aβ and tau mouse models, While Aβ GFAP-positive astrocytes were overrepresented with genes associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. Conclusion Our results offer insights into Aβ- and tau-driven specific signatures in GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte-related biomarker and suggests the need to develop context-specific astrocyte targets to study AD. Funding This study was supported by Instituto Serrapilheira, Alzheimer’s Association, CAPES, CNPq and FAPERGS.