Alzheimer’s Disease (AD) and related dementias are neurodegenerative disorders of paramount importance, in particular as medical advances continue to extend human lifespans and as the population continues to age. As of 2023, AD impacts roughly 55 million people worldwide and is projected to triple by 2050, costing trillions in healthcare expenditure and related costs. At its core, AD is a complex pathology in which it is commonly believed that amyloid β deposition leading to plaque formation and neurofibrillary tangle formation as a result of tau hyperphosphorylation are the predominant causes. As a result of these processes, there is significant neuronal dysfunction and damage, effectively leading to the cognitive deficits associated with the development of dementia. While Amyloid β and Tau are considered major instigators, however, there are also other factors at play that may be targets for mechanistic treatment of disease. Namely, cerebrovascular blood flow dysregulation and inflammation. Indeed, it has been shown that these two factors can contribute heavily to the development of AD and can be related to downstream impacts stemming from amyloid β and Tau, essentially leading to blood flow restriction, poor oxygen supply, microglial activation and microgliosis, and degradation of the blood brain barrier. Our aim is to target these processes by focusing on the inhibition of a protein known to be involved in cerebrovascular blood flow regulation and inflammation: NADPH Oxidase 2 (NOX2). NOX2 is a professional producer of reactive oxygen species (ROS) that has long been linked with inflammation and vascular regulation in other tissues and has similarly been shown to control these processes in the brain. While NOX2 largely contributes to many of these processes in a homeostatic manner, overexpression/overactivation of NOX2 (which has been seen in AD patient brain tissues) can lead to pathological consequences. Our aim is to specifically inhibit NOX2 as a mechanistic instigator of cerebrovascular dysfunction and microglial inflammation utilizing our novel, orally bioavailable, blood brain barrier penetrant small molecule NOX2 inhibitors, CPP11G and CPP11H. We will explore these processes by administering (IV/IP/PO) our inhibitors to a well-established AD mouse model, APP-PS1 mice that have been fitted with cranial windows. We will then assess mice for various features of AD such as cerebral blood flow and amyloid β deposition (Aim 1), as well as presence of inflammation by assessing microglia and microgliosis (Aim 2). We will further assess these mice by collecting tissues and utilizing biochemical tests to test for compound delivery, inflammation (e.g., IL- 1β, TNF-α, IL-6), and other mechanistic parameters of inflammation. Our overall hypothesis is that the inhibition of NOX2 by CPP11G/H will yield significant improvements in cerebrovascular blood flow dysfunction, amyloid β deposition, and microglial-associated inflammation. If successful, thes...