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.