PROJECT SUMMARY The neurodegenerative condition known as Alzheimer’s disease (AD) is increasingly placing a burden on our health care system, patients, and their families. One factor that appears to contribute to neurodegeneration, and distinguishes the development of AD from normal ageing, is cellular senescence. However, the mechanisms, causes and consequences of cellular senescence in AD and associated neuropathology remain poorly understood. A recent study demonstrated a role for the lysosomal sphingolipid enzyme acid ceramidase (AC) in ageing and senescence. Deregulation of sphingolipid metabolism has been documented in AD pathology, but the role of AC has not been explored in animal models. Depending on pH, AC catalyzes either forward or reverse reaction. Because primary lysosomal dysfunction and acidification impairment occurs AD, the increased pH potentially promotes the reverse activity of AC, which would increase the stress lipid ceramide and promote neuronal dysfunction. In this project we will test the hypothesis that acid ceramidase contributes to neurodegeneration associated with Alzheimer’s Disease. In specific aim 1, we will generate PDAPP and 5xFAD AD mice in which AC is deleted either in a neuron-specific or globally inducible manner. In specific Aim 2, we will determine how loss of AC function affects AD pathology and behavior in PDAPP and 5xFAD models. The use of neuron-specific and global AC deficient AD models will elucidate the role of the enzyme in neuronal cells and clarify how loss of AC in other cells contributes to the disease. Understanding the role of AC in AD has the potential for development of novel therapeutic strategies that combat this debilitating and costly disease.