A primary cilia–autophagy axis in hippocampal neurons is essential to maintain cognitive resilience
Blood-borne factors are essential to maintain neuronal synaptic plasticity and cognitive resilience throughout life. One such factor is osteocalcin (OCN), a hormone produced by osteoblasts that influences multiple physiological processes, including hippocampal neuronal homeostasis. However, the mechanism through which this blood-borne factor communicates with neurons remains unclear. Here we show the importance of a core primary cilium (PC) protein-autophagy axis in mediating the effects of OCN. We found that the OCN receptor GPR158 is present at the PC of hippocampal neurons and mediates the regulation of autophagy machinery by OCN. During aging, autophagy and PC core proteins are reduced in neurons, and restoring their levels is sufficient to improve cognitive impairments in aged mice. Mechanistically, the induction of this axis by OCN is dependent on the PC-dependent cAMP response element-binding protein signaling pathway. Altogether, this study demonstrates that the PC-autophagy axis is a gateway to mediate communication between blood-borne factors and neurons, and it advances understanding of the mechanisms involved in age-related cognitive decline.
Authors
- Manon Rivagorda (ORCID: https://orcid.org/0009-0001-5417-8627)
- David Romeo-Guitart (ORCID: https://orcid.org/0000-0003-3368-9302)
- Anne‐Sophie Armand (ORCID: https://orcid.org/0000-0002-0291-6421)
- Eleni Siopi (ORCID: https://orcid.org/0000-0002-2731-8540)
- Patrice Codogno (ORCID: https://orcid.org/0000-0002-5492-3180)
- Nicolas Goudin (ORCID: https://orcid.org/0000-0002-3967-4016)
- Michel Leibovici
- Étienne Morel (ORCID: https://orcid.org/0000-0002-4763-4954)
- Victoria Blanchet
- Ida Chiara Guerrera (ORCID: https://orcid.org/0000-0002-4832-6793)
- François Mailliet (ORCID: https://orcid.org/0000-0002-9813-6891)
- Eugenia Morselli (ORCID: https://orcid.org/0000-0002-7840-8351)
- Stéphanie Moriceau (ORCID: https://orcid.org/0000-0002-1413-9359)
- Franck Oury (ORCID: https://orcid.org/0000-0003-0562-9900)
- Soham Saha (ORCID: https://orcid.org/0000-0003-1173-1397)
- Valérie Boitez
- Natalie Barry
- Dimitrije Milunov
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- San Sebastián University (CL)
- Institut Necker Enfants Malades (FR)
- Institut des Maladies Génétiques Imagine (FR)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s43587-024-00791-0
- Citations
- 15
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 27.26
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation Schlumberger pour l’Education et la Recherche