Alzheimer's disease (AD) and related tauopathies are characterized by pathological Tau protein accumulation and impaired autophagy. Polyamine metabolism has emerged as a key pathway at the intersection of autophagy and Tauopathy; however, its underlying mechanisms remain poorly understood, limiting its therapeutic potential. This project focuses on spermine synthase (SMS), a critical enzyme in polyamine metabolism, whose dysregulation has been linked to autophagy defects. Our preliminary findings indicate that partial SMS reduction enhances autophagy and alleviates Tau pathology. Notably, SMS levels are elevated in the brains of AD patients, particularly in astrocytes, underscoring the importance of cell-type-specific investigations. This proposal aims to elucidate the cell-type-specific roles of SMS overexpression in polyamine metabolism and its impact on autophagy and Tau pathology. Using human glial and neuronal cell models, as well as Drosophila Tauopathy models, we will explore (1) the autonomous effects of SMS overexpression on autophagy and Tauopathy in glia and neurons, and (2) the non-autonomous effects of glial SMS overexpression on neuronal autophagy and Tauopathy. These studies will provide critical insights into the role of SMS in AD pathogenesis and identify novel therapeutic strategies, such as modulating SMS or polyamine metabolism, to restore autophagy and mitigate Tau pathology. This work establishes a foundation for understanding the interplay between cell metabolism and protein homeostasis and for developing interventions targeting cell metabolism to address autophagy deficits in neurodegenerative diseases.