PROJECT SUMMARY/ABSTRACT In the Parent R01, HL147562 (PI: Gupta), we have identified a “hyperactivated” state involving mast cell, vascular, inflammatory, and neural systems in sickle cell disease (SCD). Mast cells reside in tissues, cohabiting with nerves and vasculature, promoting direct neurovascular and neuroinflammatory interactions. Extracellular release of DNA and citrullinated histones from mast cells in a sickle microenvironment mimics extracellular traps (ETs) released by granulocytes to ensnare pathogens. In the Parent R01, we are examining how mast cell activation replete with ETs contributes to vascular dysfunction, axonal injury and increased blood brain barrier permeability leading to hyperalgesia in SCD. In this Supplement proposal, we will examine if similar mast cell activation-mediated mechanisms contribute to neuronal damage in Alzheimer's disease (AD). AD involves degeneration of hippocampal neurons and cerebellar Purkinje cells as well as abnormal neurovascular function, inflammation, and mast cell activation in the brain strikingly similar to SCD as we have demonstrated in the Parent R01. Moreover, deficits in somatosensory and sensory motor networks correlate with altered gait and motor function that precede cognitive deficits in aging and AD. Since gait instability leading to falls is a leading cause of mortality and morbidity in dementia patients, there is a critical need to understand the neurodegenerative mechanisms underlying gait changes. In humanized sickle mice we have observed activated mast cells in the parenchyma of brain and Purkinje cell degeneration in the cerebellum correlative to pain and gait changes. We hypothesize that mast cell extracellular traps contribute to vascular dysfunction and Purkinje cell damage in the cerebellum leading to gait alterations preceding cognitive changes in AD. Using mice with AD we will examine our hypothesis through 2 Specific Aims: (1) Are mast cell extracellular traps and associated vascular dysfunction elevated in AD mice, relative to WT age-matched controls? (2) Does inhibition of mast cells/traps prevent gait imbalance and neuronal and vascular alteration and attenuate the progression of AD? The novel MouseWalker System and artificial intelligence will quantify gait characteristics during normal walking, as described by PI Gupta. Since SCD and AD share similar mechanisms of hemodynamic and metabolic injury, we will examine if mast cell activation/ETs cause vascular dysfunction by monitoring cerebral perfusion and metabolism in vivo in the cerebellum and cortex of mice with AD using optical imaging technology developed by Co-Is Akbari and Wilson. We anticipate that this proof of principle proposal will demonstrate that unique traps and activation of mast cells contribute to neuronal damage and vascular dysfunction in the brain leading to impaired gait. Since gait changes precede cognitive impairment in AD, it can be used to monitor disease progression using remote sensing ...