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Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease

Author

Listed:
  • Francieli Rohden

    (University of Pittsburgh
    Universidade Federal do Rio Grande do Sul)

  • Pamela C. L. Ferreira

    (University of Pittsburgh)

  • Bruna Bellaver

    (University of Pittsburgh)

  • João Pedro Ferrari-Souza

    (University of Pittsburgh
    Universidade Federal do Rio Grande do Sul)

  • Cristiano S. Aguzzoli

    (University of Pittsburgh
    PUCRS
    University of California)

  • Carolina Soares

    (University of Pittsburgh
    Universidade Federal do Rio Grande do Sul)

  • Sarah Abbas

    (University of Pittsburgh)

  • Hussein Zalzale

    (University of Pittsburgh)

  • Guilherme Povala

    (University of Pittsburgh)

  • Firoza Z. Lussier

    (University of Pittsburgh)

  • Douglas T. Leffa

    (University of Pittsburgh)

  • Guilherme Bauer-Negrini

    (University of Pittsburgh)

  • Nesrine Rahmouni

    (Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Cécile Tissot

    (University of Pittsburgh
    Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Joseph Therriault

    (Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Stijn Servaes

    (Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Jenna Stevenson

    (Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Andrea L. Benedet

    (The Sahlgrenska Academy at the University of Gothenburg
    Sahlgrenska University Hospital)

  • Nicholas J. Ashton

    (The Sahlgrenska Academy at the University of Gothenburg
    Sahlgrenska University Hospital
    University of Gothenburg
    King’s College London)

  • Thomas K. Karikari

    (University of Pittsburgh
    The Sahlgrenska Academy at the University of Gothenburg
    Sahlgrenska University Hospital)

  • Dana L. Tudorascu

    (University of Pittsburgh
    University of Pittsburgh)

  • Henrik Zetterberg

    (The Sahlgrenska Academy at the University of Gothenburg
    Sahlgrenska University Hospital
    UCL Queen Square Institute of Neurology
    UK Dementia Research Institute at UCL)

  • Kaj Blennow

    (The Sahlgrenska Academy at the University of Gothenburg
    Sahlgrenska University Hospital)

  • Eduardo R. Zimmer

    (Universidade Federal do Rio Grande do Sul
    PUCRS
    Universidade Federal do Rio Grande do Sul
    Universidade Federal do Rio Grande do Sul)

  • Diogo Souza

    (Universidade Federal do Rio Grande do Sul)

  • Pedro Rosa-Neto

    (Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal
    McGill University)

  • Tharick A. Pascoal

    (University of Pittsburgh
    University of Pittsburgh)

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.

Suggested Citation

  • 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 & , 2025. "Glial reactivity correlates with synaptic dysfunction across aging and Alzheimer’s disease," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60806-1
    DOI: 10.1038/s41467-025-60806-1
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    References listed on IDEAS

    as
    1. Nicolai Franzmeier & Amir Dehsarvi & Anna Steward & Davina Biel & Anna Dewenter & Sebastian Niclas Roemer & Fabian Wagner & Mattes Groß & Matthias Brendel & Alexis Moscoso & Prithvi Arunachalam & Kaj , 2024. "Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Reina Bassil & Kenneth Shields & Kevin Granger & Ivan Zein & Shirley Ng & Ben Chih, 2021. "Improved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    3. Xingyu Zhang & Li Tang & Jiaolong Yang & Lanxia Meng & Jiehui Chen & Lingyan Zhou & Jiangyu Wang & Min Xiong & Zhentao Zhang, 2023. "Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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