Contribution of endothelin 1 mediated ischemic vascular dysfunction to Alzheimer's disease

Oregon Health & Science University, Portland OR

Investigators

Abstract

PROJECT SUMMARY Healthy cerebrovascular function is required to supply adequate blood flow to metabolically active brain regions. This process occurs through neurovascular coupling (NVC), where signaling between neurons, glia, and vasculature triggers an increase in local blood flow. Impairments in vascular function are present in patients with stroke and Alzheimer's disease (AD) and are commonly associated with neurological dysfunction, hypoxia, and increased amyloid beta (Aβ) pathology. AD and ischemia are closely linked, as patients with a history of stroke have an increased chance of developing dementia, while many AD patients show indications of micro-infarcts. One possible cause for this connection could be vascular dysfunction, which occurs after ischemia and is one of the earliest complications in AD. However, the mechanisms underlying ischemia- induced vascular impairments in AD are not fully defined. In pilot studies from our lab, we find that mice exposed to a mild ischemic injury demonstrate NVC dysfunction lasting up to 8 months, with more severe deficits in a mouse model of AD overexpressing Aβ. This suggests that Aβ and ischemia may have additive effects on NVC impairment. The goal of this proposal is to study the mechanism underlying this NVC impairment and its contribution to cognitive decline and AD-related pathology. A mutual feature of AD and ischemia is oxidative stress, which leads to increased production of the vasoconstrictor, endothelin-1 (ET-1). Notably, ET-1 is elevated in patients with both AD and ischemia. Aβ has also been shown to generate reactive oxygen species that promote release of ET-1. I hypothesize that after ischemia, increase in ET-1 contributes to excess constriction, compromises NVC, and contributes to the vascular dysfunction observed in AD. I will use an innovative mouse model of mixed dementia, in which Tg2576 AD model mice receive a mild ischemic stroke in early mid-life. I will administer an inhibitor of endothelin receptor A, which is responsible for ET-1-mediated constriction, for 2 months immediately after ischemia and test whether this treatment helps retain healthy NVC and cognitive function. I will assess disease progression cross-sectionally at 2 timepoints, immediately after treatment ends and 8 months following treatment, to track pathological changes through aging. Specifically, I will investigate whether ET-1 contributes to AD-associated cognitive decline (Aim 1), vascular dysfunction (Aim 2a), histopathology (Aim 2b), and hypoxia (Aim 2c) after ischemia. I expect my findings will show that endothelin receptor A inhibition reduces behavioral deficits, NVC impairment, histopathological markers of disease, and hypoxia, thus establishing a role for ET-1 in ischemia-induced vascular dysfunction in AD. These results will contribute to our understanding of chronic vascular impairment in AD and may suggest ET-1 as a viable future therapeutic target to mitigate AD-mediated decline.