Psychosocial Stress-Induced Vascular Contributions To Cognitive Impairment And Alzheimer's Disease: The Role of Xanthine Oxidase

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. This has led the NIH to prioritize studies examining vascular contributions to dementia, and its
interplay with AD. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic
stress leads to considerable cerebrovascular and neuroinflammatory 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) and uric acid. 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
and increased inflammation leading to cognitive impairment. Our central hypothesis is that chronic stress
elevates hepatic XOR, which is released into the circulation directly causing cerebrovascular dysfunction and
the activation of inflammation via a TLR4 pathway resulting in cognitive decline which accelerates dementia/AD
pathology. Aim 1 uses a liver (hepatocyte)-and endothelial-specific XOR conditional KO (HXdh-/-) mouse and a
liver-specific XOR overexpression tool to manipulate the XOR pathway during 8 weeks of chronic stress and to
examine the pathology of VCID. In Aim 2, we will use the global-and- endothelial-specific TLR4-/- mouse, along
with physiological approaches to manipulate the TLR4/NF-κB pathway, again in the context of chronic stress
and determine VCID pathology. In Aim 3, we will use the increase in XOR activity with chronic stress and switch
its bad oxidative products to nitric oxide by supplementing with nitrite and determine its actions on the pathology
of VCID. Complementary experiments will also examine the interaction of VCID and AD, by manipulating the
XOR pathway (using febuxostat) and determining if we can delay the pathological progression of AD (3xTg-AD
mice). Pilot data support this hypothesis. 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.

Grant Number: 5R01NS117754-04
NIH Institute/Center: NIH
Principal Investigator: Paul Chantler