Project Summary Recovery after ischemic stroke is one of the most critical rehabilitative medical problems in medicine. While current treatments are effective in removing clots, most patients do not present to hospitals before serious tissue damage occurs in the brain, with as many as two-thirds of stroke survivors requiring neurorehabilitation. Furthermore, post-stroke outcomes have been poorly studied in patients with cerebral amyloid angiopathy (CAA). CAA is a form of cerebrovascular disease and is characterized by substantial beta-amyloid (Aβ) accumulation within cerebral vasculature, including the blood-brain barrier (BBB). This condition exceeds amyloid deposits associated with normal aging and may contribute to age-related neurological decline. Additionally, Aβ accumulation in CAA is a risk factor for ischemic infarcts and degradation of vessel wall architecture. The integrity of vessel wall architecture is crucial for post-stroke tissue recovery since many proliferative neural progenitor cells (NPC) are close to and communicating with cerebral vasculature (BBB). This pool of proliferative NPCs that can become depleted by stroke can be mutually affected by Aβ accumulation, leading to delayed recovery of both motor and cognitive functions. We aim to understand the mechanism behind delayed post-stroke recovery because of both conditions so that targeted therapies can be proposed in the future. To study this, we will employ a transgenic 5xFAD mouse model that recapitulates Aβ accumulation in the brain to analyze CAA and cerebrovascular ischemia. The central hypothesis of this study is that Aβ accumulation in cerebral vasculature exacerbates ischemic stroke outcomes and delays post-stroke recovery by inducing BBB dysfunction and aberrant neurogenesis of NPCs. Experiments will focus on neurogenesis post-stroke, as well as microvascular function and the bioenergetic mechanisms that induce it. While there is no effective strategy to treat tissue damage following ischemic stroke and/or treat Aβ accumulation in the brain, this project focuses on the mechanism of CAA-related stroke in order to develop therapeutic strategies in the future. Defining neuropathogenesis of both CAA and ischemic stroke incidents is of significant relevance in translational medicine and clinical practice because most patients diagnosed with Alzheimer’s Disease (AD) also present with CAA; therefore, most of the disease burden due to CAA can be clinically relevant to treatments that also affect AD.