Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

De Bastiani, M. A.; Bellaver, B.; Brum, W. S.; Guerini de Souza, D.; C. L. Ferreira, P.; S. Rocha, A.; Povala, G.; Ferrari-Souza, J. P.; L. Benedet, A.; J. Ashton, N.; K. Karikari, T.; Zetterberg, H.; Blennow, K.; Rosa-Neto, P.; Pascoal, T. A.; Zimmer, E. R.; Alzheimer's Disease Neuroimaging Initiative,

doi:10.1101/2022.02.25.481812

bioRxiv · 10.1101/2022.02.25.481812

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

De Bastiani, M. A.·Bellaver, B.·Brum, W. S.·Guerini de Souza, D.·C. L. Ferreira, P.·S. Rocha, A.·Povala, G.·Ferrari-Souza, J. P.·L. Benedet, A.·J. Ashton, N.·K. Karikari, T.·Zetterberg, H.·Blennow, K.·Rosa-Neto, P.·Pascoal, T. A.·Zimmer, E. R.·Alzheimer's Disease Neuroimaging Initiative,

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Abstract

IntroductionIn Alzheimers 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-{beta} (A{beta}) or tau pathology. The molecular underpinnings behind this specificity are unexplored. Here we investigated biomarker and transcriptomic associations of GFAP-positive astrocytes with A{beta} and tau pathologies in humans and mouse models. MethodsWe studied 90 individuals with plasma GFAP, A{beta}- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting A{beta} (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. ResultsIn humans, we found that plasma GFAP associates with A{beta} but not tau pathology. Unveiling the unique nature of GFAP-positive astrocytic responses to A{beta} or tau pathology, mouse transcriptomics showed scarce overlap of DEGs between the A{beta} and tau mouse models, While A{beta} 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. ConclusionOur results offer insights into A{beta}- 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. FundingThis study was supported by Instituto Serrapilheira, Alzheimers Association, CAPES, CNPq and FAPERGS.

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De Bastiani, M. A., Bellaver, B., Brum, W. S., Guerini de Souza, D., C. L. Ferreira, P., S. Rocha, A., Povala, G., Ferrari-Souza, J. P., L. Benedet, A., J. Ashton, N., K. Karikari, T., Zetterberg, H., Blennow, K., Rosa-Neto, P., Pascoal, T. A., Zimmer, E. R., Alzheimer's Disease Neuroimaging Initiative,. 2022-02-28. Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. https://doi.org/10.1101/2022.02.25.481812

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