Neuronal antenna senses signals from the bone to sustain cognition by boosting autophagy.

Abstract

The common occurrence of cognitive decline is one of the most significant manifestations of aging in the brain, with the hippocampus - critical for learning and memory - being one of the first regions to exhibit functional deterioration. BGLAP/OCN/osteocalcin (bone gamma-carboxyglutamate protein), a pro-youth systemic factor produced by the bone, improves age-related cognitive decline by boosting hippocampal neuronal autophagy. However, the mechanism by which hippocampal neurons detect BGLAP/OCN in the systemic milieu and adapt their downstream response was previously unknown. We determined that BGLAP/OCN modulates core primary cilia (PC) proteins, suggesting that this "extracellular antenna" may play a role in mediating BGLAP/OCN's anti-aging effects. Furthermore, selective downregulation of core PC proteins in the hippocampus impairs learning and memory by reducing neuronal macroautophagy/autophagy. In contrast, restoring core PC protein levels in the hippocampus of aged mice improved this phenotype and was necessary for the induction of autophagy machinery by BGLAP/OCN. Together, these findings reveal a novel mechanism through which pro-youth systemic factors, like BGLAP/OCN, can regulate neuronal autophagy and foster cognitive resilience during aging.