Project Summary With recent advances in treatment and healthcare, life expectancy for persons following spinal cord injury (SCI) has increased substantially for several decades after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Although aging is a key risk factor for cognitive decline and incident Alzheimer’s Disease and Related Dementia (AD/ADRD), recent large-scale longitudinal population-based studies indicate that patients with SCI are at a high risk of dementia associated with substantial cognitive decline. This represents an unmet health-care challenge. However, there is a lack of information in the brain pertaining to the natural brain aging and brain aging trajectories of AD/ADRD following SCI. Such information is needed for the design of targeted, early interventions aimed at reducing the risk of cognitive decline after SCI. The autophagy-lysosomal pathway is essential for intracellular lipid, protein, and organelle degradation and quality control. Impaired autophagy is strongly implicated in accumulation of pathological protein aggregates such as phospho-tau tangles and amyloid β plaques and consequent neuronal cell damage and death in neurodegenerative diseases. Recent data indicate that age related decline in autophagy and lysosomal function in the brain was exacerbated by SCI. This was accompanied by increased brain inflammation and neurodegeneration, suggesting that perturbation of autophagy may provide a mechanistic link between SCI and AD/ADRD. Moreover, disruption of lipid homeostasis in the aged brain may contribute to autophagy defects. We hypothesize that SCI accelerates inhibition of autophagy-lysosomal function in the ageing brain through perturbation of lysosomal lipid homeostasis, ultimately aggravating long- term pathological and functional outcomes and increasing posttraumatic dementia risk. We will use young adult and aged animals with autophagy hypomorph or heperactivation to delineate the roles of autophagy-lysosomal pathway as a key regulator of brain pathology in SCI. HILIC-MS/MS based lipidomics, flow cytometry, complementary microscopy and biochemical approaches will be used in AIM 1 to determine if lipid accumulation causes lysosomal dysfunction and inhibition of autophagy in the ageing brain after SCI. AIM 2 will determine if inhibition of precision autophagy in the ageing brain after SCI leads to exacerbated inflammation and neurodegeneration increasing dementia risk. Using becn1 mutant mice with autophagy heperactivation or a naturally occurring autophagy inducer trehalose in aged mice or mice aging after SCI, AIM 3 will evaluate long-term effects of increased autophagy on proteostasis, neuroinflammation, neurodegeneration and cognitive outcomes relevant to AD/ADRD after SCI. The information gained from these highly significant and innovative studies will have an important positive impact through identifying autophagy-lysosomal...