Project Summary Recent advances in treatment and management allow many patients suffering a spinal cord injury (SCI) to live for many years after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Recent evidence, including a large-scale longitudinal population-based study, indicates that isolated SCI (without concurrent brain injury) are at a high risk of dementia associated with substantial cognitive impairments. Yet little is known about the mechanisms of SCI-induced dementia or its relationship to age of onset or age-related neurodegenerative disorders such as Alzheimer’s disease (AD). This represents an unmet health-care challenge. The autophagy-lysosomal pathway is essential for intracellular 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 plaques and consequent neuronal cell damage and death in neurodegenerative diseases. Recent data indicate that perturbation of autophagy can also alter inflammatory responses. Thus, inhibition of autophagy-lysosomal function could contribute to both neuronal cell damage and inflammation observed in age-related AD/ADRD. The purpose of this study is to identify the key mechanisms involved in critical yet largely ignored brain changes after SCI and test the hypothesis that SCI accelerates inhibition of autophagy-lysosomal function in the brain, ultimately promoting brain neurodegeneration and neuroinflammation and leading to dementia. We will use young adult autophagy deficient mice and aged animals to delineate the roles of autophagy-lysosomal pathway as a key regulator of brain inflammation and neurodegeneration in SCI. Aim 1 will determine whether progressive age-related disruption of the autophagy-lysosomal function in the brain is accelerated following SCI. Multiple quantitative assessments of autophagy flux, lysosomal function, inflammation, and neurodegeneration will be combined with characterization of dementia-like functional outcomes to test the hypothesis that SCI at chronic phase leads to accelerated inhibition of autophagy- lysosomal function in the brain, contributing to neuroinflammation and neurodegeneration associated with cognitive decline. Aim 2 will determine the influence of age on the autophagy-lysosomal function in SCI- mediated dementia. Aged C57BL/6 mice subjected to SCI will be used to address the influence of age on SCI-mediated dysregulation of the autophagy-lysosomal function, AD-like neuropathology, and neurodegeneration in the brain, and associated cognitive impairments. Since the scope of our current R01 grant is limited to short-term assessment of autophagy-lysosomal function in the injury site after acute SCI, we request additional funds to collect long-term data necessary to test this hypothesis. We expect to use these data to support eventual R01 applicatio...