Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Introduction In Alzheimer’s disease clinical research, glial fibrillary acidic protein (GFAP) released in the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was recently demonstrated that plasma GFAP levels are associated with amyloid-β (Aβ) but not 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. Findings In humans, we found that plasma GFAP associates with Aβ but not tau pathology. Supporting these results, mouse transcriptomics showed scarce overlap of DEGs between the Aβ and tau mouse models, revealing the unique nature of GFAP-positive astrocytic responses to Aβ or tau pathology. 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. Interpretation 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. Evidence before the study The glial fibrillary acidic protein (GFAP) is commonly used as a proxy of reactive astrogliosis in Alzheimer’s disease (AD) clinical studies. Recent evidence demonstrated that increases in GFAP levels are associated with a specific aspect of AD pathology, namely amyloid-β (Aβ). However, the biological interpretation behind it was not explored in depth molecularly. Uncovering the phenotypes acquired by GFAP-positive astrocytes under Aβ or tau influence might directly impact clinical research by improving the biological interpretation of clinical glial biomarkers used in AD. Added value of this study This study revealed molecular signatures driven by AD hallmarks in hippocampal GFAP-positive astrocytes, including 1) a scarce overlap of differentially expressed genes (DEG) driven by Aβ and tau; 2) abnormalities in proteostasis and exocytosis-related processes in Aβ-driven reactive astrocytes and 3) impaired DNA/RNA processing and cytoskeleton dynamics in tau-driven astrocytes. Additionally, this study revealed several astrocyte-related DEGs and biological pathways specific to each aspect of AD core pathology. Implications of all the available evidence These results shed light on the existence of GFAP-positive astrocyte signatures driven by Aβ- and tau pathologies in AD. Characterizing how upstream triggers influence GFAP-positive astrocyte molecular signals may contribute to the biological interpretation of GFAP as a biomarker of AD. Additionally, the signature genes and related biological processes identified in this study might guide other studies to identify context-specific astrocyte biomarkers for AD. Finally, it paves the way to unraveling novel mechanisms and therapeutic targets capable of potentiating the effects of emerging anti and anti-tau therapies.