CYP2C11 Overexpression targeting peri-lesion astrocytes to improve cognitive function in mice with multi-infarct dementia

PROJECT SUMMARY Multi-infarct dementia (MID), the most prevalent vascular cognitive impairment and dementia (VCID) subtype, lacks disease-modifying therapies. Here, we propose a novel strategy to enhance cerebral blood flow (CBF) and suppress neuroinflammation in MID. Astrocyte-derived epoxyeicosatrienoic acids (EETs), potent vasodilators and anti-inflammatory mediators, are downregulated in response to hypoperfusion and hypoxia. Employing adeno-associated virus (AAV) serotype PhP.eB driven by the glial fibrillary acidic protein (GFAP) promoter, we propose to overexpress CYP2C11, a key EET-generating enzyme, specifically in peri-lesion astrocytes, via utilizing the regional upregulation of GFAP in reactive astrocytes surrounding ischemic lesions. Localized EET production will promote vasodilation, increase CBF in hypoperfused regions, and potentially improve cognitive function. Additionally, EETs' anti-inflammatory properties can mitigate neuroinflammation, a key contributor to MID progression. This targeted approach offers promise to improve therapeutic efficacy and to minimize off- target effects of systemic vasodilators. We will test the following three specific aims in middle-aged mice: Aim 1 will determine the optimal dose of AAV-PhP.eB-GFAP-CYP2C11 on EET production, CBF, neuroinflammation, and cognitive function in MID; Aim 2 will investigate the long-term effects of targeted CYP2C11 overexpression in MID; Aim 3 will validate the causal contribution of targeted CYP2C11 overexpression on cognitive function in MID. Our strategy presents a groundbreaking approach for MID treatment, with potential therapeutic impact on other neurovascular disorders.