Interplay of neuropeptide Y and autophagy in Alzheimer's disease: Therapeutic perspectives and mechanistic insights

Alzheimer's disease (AD) is a progressive, chronic, neurodegenerative disorder involving cognitive impairment, neuronal loss, autophagy dysregulation, and toxic protein aggregates build-up, including amyloid-β plaques and hyperphosphorylated tau tangles. Autophagy dysregulation is a central driving force behind AD pathogenesis, interfering with the clearance of these aggregates and resulting in synaptic disruption and enhanced neurodegeneration. Neuropeptide Y (NPY) is abundantly present in the CNS. NPY has been identified as a promising candidate due to its neuropeptidergic activity. It plays a central role in regulating autophagy, anti-inflammation, and the induction of synaptic plasticity. NPY regulates the AMPA-mTOR pathway to restore cellular homeostasis and enhance neuronal survival through improved autophagic flux. It facilitates the clearance of aggregate proteins and dysfunctional cellular components, which lessen the signs of AD pathology. Moreover, NPY plays an important role in stabilizing the mitochondria and enhancing antioxidant action, in effect sustaining cognitive function. The modulatory influence of NPY on autophagy represents a potential novel direction in AD therapy, advanced delivery systems, such as nanoparticle-based carriers, offer promising targeted brain delivery mechanisms. However, clinical application is hindered by the need for a receptor-specific agonist to mitigate side effects and the lengthy trials necessary to assess long-term efficiency. Further research should aim to optimise NPY delivery and autophagy-targeted therapies to develop more effective treatments; such research challenges may position NPY as a breakthrough candidate for slowing cognitive and functional impairment in AD.