Giovanna Cazzolla, David Toppe, Gina Krause, Gaga Kochlamazashvili, Janine Lützkendorf, Ina M Schedina, Heike Stephanowitz, Anna Maria Reisenbichler, Xingxiang Chen, Yannic Kerkhoff, Eric Reifenstein, Helen M Ernst, Max von Kleist, Andreas Zimmermann, Tobias Eisenberg, Frank Madeo, Fan Liu, Herbert Herzog, Anne Albrecht, Dietmar Schmitz, Volker Haucke, Stephan J Sigrist, Marta Maglione
Macroautophagy/autophagy is a critical cellular degradation pathway essential for neuronal proteostasis and synaptic function. Its decline with aging is associated with synaptic dysfunction and reduced circuit resilience. NPY (neuropeptide Y), a highly abundant brain neuropeptide, has emerged as an important regulator of autophagy and aging-related processes. In Drosophila, the NPY-family peptide sNPF modulates age-related changes in presynaptic architecture via non-cell autonomous mechanisms. Here, we examined whether autophagy and NPY interact within hypothalamic NPY+ AGRP+ neurons to regulate presynaptic organization in distant brain regions. We show that autophagy in these neurons non-cell autonomously controls hippocampal presynaptic active zone architecture and proteostasis, while maintaining NPY peptide levels. Importantly, dietary supplementation of the natural polyamine spermidine restored NPY expression in the aged hippocampus, highlighting its potential to rejuvenate neuropeptide signaling. Together, these findings reveal a pathway by which hypothalamic autophagy and NPY signaling regulate hippocampal synaptic architecture, linking metabolic state to synaptic resilience.