De Bastiani, MA;
Bellaver, B;
Brum, WS;
Souza, DG;
Ferreira, PCL;
Rocha, AS;
Povala, G;
... Zimmer, ER; + view all
(2023)
Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies.
Brain, Behavior, and Immunity
, 110
pp. 175-184.
10.1016/j.bbi.2023.03.001.
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Abstract
Introduction: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked 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 pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal 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 conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, 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 hippocampal GFAP-positive astrocytic responses to Aβ or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aβ. and tau mouse models. While Aβ GFAP-positive astrocytes were overrepresented with DEGs 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 hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers 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.
| Type: | Article |
|---|---|
| Title: | Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies |
| Location: | Netherlands |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bbi.2023.03.001 |
| Publisher version: | https://doi.org/10.1016/j.bbi.2023.03.001 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Alzheimer’s disease, Amyloid, Biomarker, GFAP, Tau, Humans, Mice, Animals, Astrocytes, Glial Fibrillary Acidic Protein, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Hippocampus, tau Proteins |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10168691 |
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