Non-cell autonomous control of presynaptic remodeling by the hypothalamic autophagy/NPY axis

Abstract Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expressed neuropeptide in the mammalian brain, has emerged as a key modulator of both autophagy and aging-related processes. In Drosophila, the NPY-family peptide short Neuropeptide F (sNPF) has been shown to causally influence aging-associated changes in synaptic architecture and function, particularly at the presynaptic active zone (AZ), via non-cell autonomous mechanisms. Extending this concept to mammals, we investigated whether NPY and autophagy interact within NPY-secreting neurons to regulate age-related AZ remodeling. Our results indicate that hypothalamic NPY/AgRP neurons may exert geroprotective effects through the release of NPY and potentially other signaling molecules, thereby influencing both metabolic homeostasis and brain-wide synaptic function. These data suggest a conserved role for autophagy in maintaining presynaptic organization and resilience during aging. Competing Interest Statement SJS has equity interests in TLL (The Longevity Labs), a company founded in 2016 that develops natural food extracts. Abbreviations - AgRP - Agouti-related peptide - ATG5 - autophagy related 5 - AZ - active zone - BRP - Bruchpilot - Bsn - Bassoon - CA3-CA1 - Cornu Ammmonis 3-Cornu Ammonis 1 - cKO - conditional knockout - KO - knockout - LC3 - microtubule associated protein 1 light chain 3 - MB - Mushroom Body - MF-CA3 - Mossy Fiber-Cornus Ammonis 3 - NPY - neuropeptide Y - PreScale - presynaptic upscaling - RIM-BP2 - RIM-Binding protein 2 - SQSTM1/p62 - sequestosome-1 - sNPF - short Neuropeptide F - Spd - spermidine - Spd-S - spermidine supplementation