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Cited by 57Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

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De Bastiani, Marco Antônio, Bellaver, Bruna, Brum, Wagner S., Souza, Debora G., Ferreira, Pamela C.L., Rocha, Andreia S., Povala, Guilherme, Ferrari-Souza, João Pedro +8 more·2023·Brain, Behavior, and Immunity
DOI 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.

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  • Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs.

    “Previous transcriptomic studies comparing AD mouse models have reported similarities and differences in astrocyte responses to Aβ plaques versus pTau NFTs5,7,33.”

    From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [33]

    The Introduction and results describe a transcriptomic comparison of hippocampal GFAP-positive astrocytes from PS2APP amyloidosis and Tau P301S mouse models, finding a small overlap of differentially expressed genes and distinct responses. The Discussion also reports inflammation-related changes in both models. The paper frames the comparison as Aβ versus tau pathology; the cited passages do not establish responses specifically to Aβ plaques versus phosphorylated-tau neurofibrillary tangles. (LLM, conf=0.82)

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Authors
De Bastiani, M. A., Bellaver, B., Brum, W. S., Souza, D. G., Ferreira, P. C. L., Rocha, A. S., Povala, G., Ferrari-Souza, J. P., Benedet, A. L., Ashton, N. J., Karikari, T. K., Zetterberg, H., Blennow, K., Rosa-Neto, P., Pascoal, T. A., & Zimmer, E. R.
Affiliations
  • Universidade Federal do Rio Grande do Sul (BR)
  • King's College London (GB)
  • University of Pittsburgh (US)
  • Sahlgrenska University Hospital (SE)
Corresponding author
Zimmer, Eduardo R.
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2023-05
Volume
110
Pages
175-184
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2023.03.001
OpenAlex
W4323046962
Cited by
57
References
61
Citations by year
2026: 9 · 2025: 15 · 2024: 20 · 2023: 11 · 2022: 2
FWCI
7.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • BrightFocus Foundation
  • European Research Council
  • National Academy of Neuropsychology
  • Fonds de recherche du Québec Santé
  • CAPES
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Institute on Aging
  • Alzheimer's Association
  • ADDF
  • Instituto Serrapilheira
  • UK Dementia Research Institute
  • Olav Thon Stiftelsen
  • FAPERGS
  • Swedish Research Council
  • Agneta Prytz-Folkes Och Gosta Folkes Stiftelse
  • International Society for Neurochemistry
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, glial fibrillary acidic protein, astrocytes, amyloid-beta, tau pathology, reactive astrogliosis, hippocampus, differentially expressed genes, proteostasis, exocytosis, cytoskeletal dynamics
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Mice

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