ABSTRACT
Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia
behind Alzheimer's disease (AD), and is a frequent co-morbidity with AD. Furthermore, the deleterious effect of
vascular pathologies combined with AD pathology leads to increased likelihood of dementia. Despite the
importance of VCID, little is known about its molecular mechanisms underlying vascular and cognitive
dysfunction. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic
stress leads to considerable cerebrovascular changes that have similar fundamental changes evident in the
progression of AD has led us to focus on this process. Endothelial dysfunction is a critical determinant of vascular
disease and predictor of clinical events. Xanthine oxidoreductase (XOR) is a major source of oxidative products
(hydrogen peroxide and superoxide). The liver is the site of greatest XOR activity and the main source of
circulating XOR activity. As such, XOR can negatively affect the vasculature. Our preliminary data suggest that
chronic stress increases XOR activity resulting in cerebrovascular dysfunction. Our central hypothesis is XOR
amplification due to stress will directly cause cerebrovascular dysfunction, leading to cognitive decline
and the acceleration of dementia/AD pathology. Aim 1 uses liver-specific Xdh (HXO), vascular-specific Xdh
(EndoXO), and double liver-vascular specific Xdh (H&EXO) conditional knockout models (loss of function) to
identify the contribution of liver and vascular derived XOR and its actions on cerebrovascular and cognitive
function. In Aim 2, we will determine the role of XOR on dementia/AD pathology and progression. We will: 1) use
our Xdh (liver, vascular, liver & vascular) conditional knockout models (loss of function) combined with a model
of VCID (asymmetric common carotid artery occlusion surgery with an ameroid constrictor, ACAS), to induce
chronic cerebral hypoperfusion; and 2) in our 3xTg-AD mice we will block XOR production (with Febuxostat; loss
of function) and increase XOR activity with our XDH adeno-associated virus (AAV; gain of function). These
models will allow us to directly test the role of XOR and its actions on cerebrovascular and cognitive function. As
with aim 1, I will measure cerebrovascular function and structure, oxidative products, cognitive function, and
other AD-related pathologies (Tau, amyloid-ß etc).Thus, the overall goal of these studies is to determine the
etiology of the stress-related XOR and pro-inflammatory changes in mediating VCID, and its progression to AD
pathology. The studies will fill gaps identified by the NIH regarding the need for understanding of vascular
contributions to cognitive impairment and dementia.