Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease
Abstract Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunct...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60806-1 |
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| author | Francieli Rohden Pamela C. L. Ferreira Bruna Bellaver João Pedro Ferrari-Souza Cristiano S. Aguzzoli Carolina Soares Sarah Abbas Hussein Zalzale Guilherme Povala Firoza Z. Lussier Douglas T. Leffa Guilherme Bauer-Negrini Nesrine Rahmouni Cécile Tissot Joseph Therriault Stijn Servaes Jenna Stevenson Andrea L. Benedet Nicholas J. Ashton Thomas K. Karikari Dana L. Tudorascu Henrik Zetterberg Kaj Blennow Eduardo R. Zimmer Diogo Souza Pedro Rosa-Neto Tharick A. Pascoal |
| author_facet | Francieli Rohden Pamela C. L. Ferreira Bruna Bellaver João Pedro Ferrari-Souza Cristiano S. Aguzzoli Carolina Soares Sarah Abbas Hussein Zalzale Guilherme Povala Firoza Z. Lussier Douglas T. Leffa Guilherme Bauer-Negrini Nesrine Rahmouni Cécile Tissot Joseph Therriault Stijn Servaes Jenna Stevenson Andrea L. Benedet Nicholas J. Ashton Thomas K. Karikari Dana L. Tudorascu Henrik Zetterberg Kaj Blennow Eduardo R. Zimmer Diogo Souza Pedro Rosa-Neto Tharick A. Pascoal |
| author_sort | Francieli Rohden |
| collection | DOAJ |
| description | Abstract Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration. |
| format | Article |
| id | doaj-art-059d1cb6fc4c4975b846db2b5b05316e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-059d1cb6fc4c4975b846db2b5b05316e2025-08-20T03:03:41ZengNature PortfolioNature Communications2041-17232025-07-0116111010.1038/s41467-025-60806-1Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s diseaseFrancieli Rohden0Pamela C. L. Ferreira1Bruna Bellaver2João Pedro Ferrari-Souza3Cristiano S. Aguzzoli4Carolina Soares5Sarah Abbas6Hussein Zalzale7Guilherme Povala8Firoza Z. Lussier9Douglas T. Leffa10Guilherme Bauer-Negrini11Nesrine Rahmouni12Cécile Tissot13Joseph Therriault14Stijn Servaes15Jenna Stevenson16Andrea L. Benedet17Nicholas J. Ashton18Thomas K. Karikari19Dana L. Tudorascu20Henrik Zetterberg21Kaj Blennow22Eduardo R. Zimmer23Diogo Souza24Pedro Rosa-Neto25Tharick A. Pascoal26Department of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-MontréalDepartment of Psychiatry, School of Medicine, University of PittsburghTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-MontréalTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-MontréalTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-MontréalDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry, School of Medicine, University of PittsburghDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of GothenburgDepartment of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of GothenburgGraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do SulGraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do SulTranslational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Hospital Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-MontréalDepartment of Psychiatry, School of Medicine, University of PittsburghAbstract Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic markers (GAP43, neurogranin). CSF GFAP levels were associated with presynaptic and postsynaptic dysfunction, independent of cognitive status or Aβ presence. CSF sTREM2 levels were related to presynaptic markers in cognitively unimpaired and impaired Aβ+ individuals, and to postsynaptic markers in cognitively impaired Aβ+ individuals. Notably, CSF pTau mediated the relationships between GFAP or sTREM2 and synaptic dysfunction. Our findings, validated in two independent cohorts (TRIAD and ADNI), reveal a distinct pattern of glial contribution to synaptic degeneration.https://doi.org/10.1038/s41467-025-60806-1 |
| spellingShingle | Francieli Rohden Pamela C. L. Ferreira Bruna Bellaver João Pedro Ferrari-Souza Cristiano S. Aguzzoli Carolina Soares Sarah Abbas Hussein Zalzale Guilherme Povala Firoza Z. Lussier Douglas T. Leffa Guilherme Bauer-Negrini Nesrine Rahmouni Cécile Tissot Joseph Therriault Stijn Servaes Jenna Stevenson Andrea L. Benedet Nicholas J. Ashton Thomas K. Karikari Dana L. Tudorascu Henrik Zetterberg Kaj Blennow Eduardo R. Zimmer Diogo Souza Pedro Rosa-Neto Tharick A. Pascoal Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease Nature Communications |
| title | Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease |
| title_full | Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease |
| title_fullStr | Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease |
| title_full_unstemmed | Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease |
| title_short | Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease |
| title_sort | glial reactivity correlates with synaptic dysfunction across aging and alzheimer s disease |
| url | https://doi.org/10.1038/s41467-025-60806-1 |
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