Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer’s disease
Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([<sup>18</sup>F]AZD4694), tau aggregation ([<sup>18</sup>F]MK-6240) and microglial activation ([<sup>11</sup>C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.
Authors
- Wyllians Vendramini Borelli (ORCID: https://orcid.org/0000-0001-9282-0601)
- Dana Tudorascu (ORCID: https://orcid.org/0000-0003-4675-3692)
- Serge Gauthier (ORCID: https://orcid.org/0000-0003-4272-3330)
- Tharick Ali Pascoal (ORCID: https://orcid.org/0000-0001-9057-8014)
- João Pedro Ferrari‐Souza (ORCID: https://orcid.org/0000-0003-2183-1551)
- Joseph Therriault (ORCID: https://orcid.org/0000-0002-7826-4781)
- Nicholas James Ashton (ORCID: https://orcid.org/0000-0002-3579-8804)
- Guilherme Povala (ORCID: https://orcid.org/0000-0002-2023-6569)
- Douglas Teixeira Leffa (ORCID: https://orcid.org/0000-0002-4890-8451)
- Eduardo Rigon Zimmer (ORCID: https://orcid.org/0000-0002-5349-0053)
- Kaj Blennow (ORCID: https://orcid.org/0000-0002-1890-4193)
- Wagner S. Brum (ORCID: https://orcid.org/0000-0002-9777-0559)
- Giovanna Carello‐Collar (ORCID: https://orcid.org/0000-0003-4644-0151)
- Lucas Porcello Schilling (ORCID: https://orcid.org/0000-0002-9923-6982)
- Mychael V. Lourenco (ORCID: https://orcid.org/0000-0002-1078-0296)
- Nesrine Rahmouni (ORCID: https://orcid.org/0009-0004-3081-8468)
- Marco Antônio De Bastiani (ORCID: https://orcid.org/0000-0003-3924-5278)
- Pâmela C.L. Ferreira (ORCID: https://orcid.org/0000-0003-2134-9829)
- Arthur C. Macedo (ORCID: https://orcid.org/0000-0002-3957-0284)
- Ilaria Pola (ORCID: https://orcid.org/0000-0003-2090-2944)
- Stijn Servaes (ORCID: https://orcid.org/0000-0003-3565-1930)
- Bruna Bellaver (ORCID: https://orcid.org/0000-0002-2212-3373)
- Gallen Triana‐Baltzer (ORCID: https://orcid.org/0000-0003-0612-1236)
- Firoza Zubeida Lussier (ORCID: https://orcid.org/0000-0002-6877-4825)
- Cristiano Schaffer Aguzzoli (ORCID: https://orcid.org/0000-0002-7378-3830)
- Hartmuth C. Kolb (ORCID: https://orcid.org/0000-0003-2414-5792)
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Sterling C. Johnson (ORCID: https://orcid.org/0000-0002-8501-545X)
- Diogo O. Souza (ORCID: https://orcid.org/0000-0002-4322-0404)
- Pedro Rosa‐Neto (ORCID: https://orcid.org/0000-0001-9116-1376)
- Andréa L. Benedet
- Jenna Stevenson (ORCID: https://orcid.org/0000-0003-2848-1451)
Institutions
- Universidade Federal do Rio de Janeiro (BR)
- University of Science and Technology of China (CN)
- Montreal Neurological Institute and Hospital (CA)
- Universidade Federal do Rio Grande do Sul (BR)
- Johnson & Johnson (United States) (US)
- University of Wisconsin–Madison (US)
- University of Arizona (US)
- University of Pittsburgh (US)
- Sahlgrenska University Hospital (SE)
- Sorbonne Université (FR)
- Instituto do Cérebro (BR)
- Hospital Moinhos de Vento (BR)
- Southwestern Medical Center (US)
- Enigma Diagnostics (United Kingdom) (GB)
- Pitié-Salpêtrière Hospital (FR)
- UK Dementia Research Institute (GB)
- Banner Sun Health Research Institute (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Institut du Cerveau (FR)
- University College London (GB)
- Pontifícia Universidade Católica do Rio Grande do Sul (BR)
- McGill University (CA)
- The University of Texas Southwestern Medical Center (US)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1038/s41593-025-02103-0
- Citations
- 6
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 5.05
Funders
- McGill University
- Stiftelsen för Gamla Tjänarinnor
- Weston Brain Institute
- National Institute for Health and Care Research
- University College London
- Vetenskapsrådet
- UK Dementia Research Institute
- National Institutes of Health