Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer’s disease model
Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity, we report the presence of three astrocyte subpopulations defined by their signaling activity, in the prefrontal cortex of male APP/PS1dE9 mice. These subpopulations are not triggered by amyloid deposition and are also observed in wild-type mice. They show distinct morphologies, molecular signatures and functional profiles. While NF-kB+ astrocytes have larger territories and higher lysosomal activity, STAT3+ astrocytes display enhanced hemichannel activity. Specific inhibition of these subpopulations reduces amyloid plaque size and impacts anxiety, social preference and social memory in AD but not wild-type mice. Our results show how innate signaling shapes astrocyte subpopulations in the mouse cortex, with distinct functions in health and disease.
Authors
- Carole Escartin (ORCID: https://orcid.org/0000-0003-3613-4118)
- Nathalie Déchamps
- María-Angeles Carrillo-de Sauvage (ORCID: https://orcid.org/0000-0002-3312-5956)
- Yiannis Poulot-Becq-Giraudon (ORCID: https://orcid.org/0000-0003-3871-9259)
- Ludmila Juricek (ORCID: https://orcid.org/0000-0002-0650-8046)
- Kévin Muret (ORCID: https://orcid.org/0000-0003-3988-7772)
- Fanny Petit (ORCID: https://orcid.org/0000-0003-2757-3434)
- Martine Guillermier
- Céline Derbois
- Océane Guillemaud
- Éric Bonnet (ORCID: https://orcid.org/0000-0002-8468-2867)
- Nathalie Rouach (ORCID: https://orcid.org/0000-0002-5574-888X)
- Pauline Gipchtein
- Tony Barbay
- Giampaolo Milior (ORCID: https://orcid.org/0009-0000-4318-6923)
- Alexis‐Pierre Bemelmans (ORCID: https://orcid.org/0000-0001-7605-5225)
- Rémi Bos (ORCID: https://orcid.org/0000-0003-2639-3271)
- Solène Brohard (ORCID: https://orcid.org/0000-0002-0209-5467)
- Noëlle Dufour
- Elisa Degl’Innocenti (ORCID: https://orcid.org/0000-0002-3819-0116)
- Marie‐Claude Gaillard
- Miriam Riquelme‐Perez (ORCID: https://orcid.org/0000-0002-9204-3088)
- Karouna Bascarane
- Léa Siron
- Tom Lakomy
- Gwennaëlle Aurégan
- Lucile Benhaim
- Vivien Letenneur
- Mie Møller Clausen (ORCID: https://orcid.org/0009-0001-4241-5760)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Centre National de Recherche en Génomique Humaine (FR)
- Institut des Neurosciences Paris-Saclay (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- CEA Paris-Saclay (FR)
- Institut de Neurosciences de la Timone (FR)
- Institut de Radiobiologie Cellulaire et Moléculaire (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1038/s41467-026-71826-w
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Association France Alzheimer
- Centre National de la Recherche Scientifique
- Université de Recherche Paris Sciences et Lettres