Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Marco Antônio De Bastiani; Bruna Bellaver; Wagner S Brum; Debora G Souza; Pamela C L Ferreira; Andreia S Rocha; Guilherme Povala; João Pedro Ferrari-Souza; Andrea L Benedet; Nicholas J Ashton; Thomas K Karikari; Henrik Zetterberg; Kaj Blennow; Pedro Rosa-Neto; Tharick A Pascoal; Eduardo R Zimmer; Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.bbi.2023.03.001

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies

Brain Behav Immun. 2023 May:110:175-184. doi: 10.1016/j.bbi.2023.03.001. Epub 2023 Mar 4.

Authors

Marco Antônio De Bastiani¹, Bruna Bellaver², Wagner S Brum³, Debora G Souza⁴, Pamela C L Ferreira⁵, Andreia S Rocha¹, Guilherme Povala², João Pedro Ferrari-Souza², Andrea L Benedet⁶, Nicholas J Ashton⁷, Thomas K Karikari⁸, Henrik Zetterberg⁹, Kaj Blennow¹⁰, Pedro Rosa-Neto¹¹, Tharick A Pascoal⁵, Eduardo R Zimmer¹²; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
² Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
³ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁴ Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Brain Institute of Rio Grande do Sul, PUCRS, Porto Alegre, RS, Brazil.
⁵ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁷ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁸ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁹ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹⁰ Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹¹ Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging (MCSA), Douglas Mental Health University Institute, Departments of Neurology and Neurosurgery, Psychiatry, and Pharmacology, McGill University, Montreal, Canada.
¹² Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Brain Institute of Rio Grande do Sul, PUCRS, Porto Alegre, RS, Brazil. Electronic address: [email protected].

PMID: 36878332
DOI: 10.1016/j.bbi.2023.03.001

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.

Keywords: Alzheimer’s disease; Amyloid; Biomarker; GFAP; Tau.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Astrocytes* / metabolism
Biomarkers / metabolism
Glial Fibrillary Acidic Protein / metabolism
Hippocampus / metabolism
Humans
Mice
tau Proteins / metabolism

Substances

Glial Fibrillary Acidic Protein
Amyloid beta-Peptides
Biomarkers
tau Proteins