BBB and neurovascular function modulation by endothelial NOX1 in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive age-associated brain disorder and the leading cause of dementia and disability in the elderly worldwide. While AD is generally associated with tau and amyloid beta (Aβ) accumulation, concurrent derangements in cerebral blood flow (CBF) and neurovascular coupling have been demonstrated both in patients and mice AD models. Cerebral vascular dysfunction is an early event in the AD pathology progression that creates a permissive environment for oxidative damage. Oxidative stress has been shown to link Aβ accumulation and neurovascular damage. NADPH oxidases (NOXs) are key sources of reactive oxygen species (ROS) in neurovascular cells and have been shown to play an important role in neurodegenerative diseases. Increased NOX activity was found in the brain tissue of animal models of neurodegenerative diseases and in post-mortem brains of AD patients. NOX1 has been identified as a key factor in the loss of barrier function in the brain endothelial cells exposed to Aβ. Importantly, our preliminary data showed increased NOX1 expression and activity in the brain of aged 3xTgAD mouse model of AD, that was ameliorated via endothelial cell specific targeting of NOX1. Endothelial NOX1 is therefore a promising target for the development of neuroprotective agents in the fight against AD. The cellular sources of NOX1 and the mechanisms by which NOX1 may promote vascular damage in AD have not been fully elucidated. We will inhibit NOX1 specifically in endothelial cells (via cell specific targeting virus developed in our viral core) or globally (via NOX1 specific inhibitor) to dissect the specific contribution of endothelial NOX1 (via global inhibitor ML171 or endothelial specific AAV-shNOX1) can decrease production of reactive oxygen species, maintain BBB integrity, and enhance neurovascular coupling and preserve CBF in aged 3xTg-AD mice. Delineating the specific role of oxidative damage via endothelial derived NOX1 on BBB dysfunction, and neurovascular coupling impairment can offer new therapeutic strategies and evaluate the possibility of targeting brain vasculature in the treatment of neurodegenerative diseases.