Title: Immunometabolic regulation after CNS injury Progressive neurodegeneration is a sequela of traumatic brain injury (TBI), with ~2% of the population living with chronic neurological deficits, including cognitive impairment and dementia, caused by a prior head injury. Epidemiological data indicate a history of TBI is the leading extrinsic cause of dementia, including a heightened risk of developing Alzheimer’s disease and related dementias (AD/ADRD); however, the mechanisms linking TBI with subsequent neurodegeneration including due to vascular contribution to cognitive impairment and dementia (VCID) are undefined. Despite immune privilege within the CNS, development of a coordinated series of spatially- and temporally-regulated cerebral immune responses correlates with premature cognitive aging, neurodegeneration and VCID after TBI. Our objective is to test the overarching hypothesis that cerebral metabolic dysregulation activates meningeal innate lymphoid cells (ILCs) to perpetuate a chronic, pro-inflammatory cascade that culminates in neurodegeneration and poor cognitive outcomes. Specifically, we propose that reduced activity of the energetic sensor, 5’-AMP-activated protein kinase (AMPK), induces a senescence-associated secretory phenotype (SASP) within astrocytes to expand pro-inflammatory ILCs, recruit peripheral immune cells, and drive post-traumatic dementia. Aim 1 will test the hypothesis that astrocyte-specific AMPK activation limits neurodegeneration. Studies will incorporate advanced genetic models, neuroimaging, and spatial proteogenomics to longitudinally define region- and cell type-specific neurodegenerative changes after TBI. Aim 2 will test the hypothesis that astrocyte-specific AMPK activation restrains pro-inflammatory meningeal ILC expansion. Studies will functionally implicate meningeal ILCs as critical mediators of cerebral immunity and progressive neurodegeneration, including cerebral atrophy and grey/white matter loss, after TBI. Aim 3 will test the hypothesis that regulatory ILC2 reduce the progressive neurodegenerative profile to attenuate chronic neurological injury after TBI. Studies will demonstrate the therapeutic potential of targeting meningeal ILCs to restrain neurodegeneration. Expected outcomes: Our mechanistic studies will show acute cerebral metabolic derangements initiate a deleterious, pro-inflammatory cascade that culminates in neurodegeneration. Specifically, our conceptually innovative studies will identify astrocyte senescence as a cellular convergence point that integrates cerebral metabolism and chronic inflammation. We also will elucidate a novel route of cell-cell communication whereby astrocytes coordinate peripheral immunity via regulation of meningeal ILCs. Together, our studies will show how local pathological changes within the CNS are translated into context-specific immune responses that culminate in post-traumatic dementia. Clinical significance: Progressive neurodegeneration causes ch...