Neurovascular astrocyte dysfunction in VCID

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Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD). In addition, VCID is a frequent co-morbidity with AD, complicating the diagnosis and treatment of AD for a significant proportion of AD patients. Despite its prevalence, VCID remains relatively understudied compared to AD, and little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. In part, this is due to the multiple pathological processes disrupting neurovascular networks that can result in VaD. We have previously shown that astrocytic end-feet are significantly impacted in the presence of cerebral amyloid angiopathy (CAA), with decreased contact of astrocytic end-feet with the vasculature. Further, these morphological changes in the astrocyte were associated with decreased expression of aquaporin 4, Kir4.1 and BK channels at the astrocytic end-feet. We have developed a model of VCID through the induction of hyperhomocysteinemia (HHcy). We have shown that this model in wildtype mice is associated with multiple microhemorrhages, reduced blood flow, neuroinflammation and cognitive impairment. We now have intriguing preliminary data that indicates these same pathological changes in the astrocytes that we observed with CAA also occur in our HHcy model of VCID. In this research proposal we will use the HHcy model of VCID. We will test the hypothesis that astrocyte end-foot disruption contributes to neuronal dysfunction and that the activation of MMP9 in the HHcy model is critical to the disruption of the astrocytic end-feet. We have developed 3 specific aims. Aim 1. Test the hypothesis that astrocytic end-foot disruption leads to neuronal dysfunction and impaired potassium homeostasis. Aim 2. Test the hypothesis that MMP9 is an essential mediator of astrocyte end-foot detachment from the cerebrovasculature with VCID. Aim 3. Test the hypothesis that astrocytic end-foot disruption is a common pathological characteristic of cerebrovascular pathologies of VCID.