Aging and hypertension are primary risk factors for the development of cerebral vascular disease (CVD), stroke, vascular cognitive impairment (VCI), and Alzheimer?s disease (AD). However, the genes and pathways determining genetic susceptibility are unknown. In preliminary studies, Dr. Roman?s lab identified sequence variants in t h e CYP4A11 and 4F2 genes, which inhibit the formation of 20-HETE, are associated with loss of hippocampal and AD signature region volumes, and cognitive dysfunction in 4,286 elderly patients in the Atherosclerosis Risk in Communities-Neurocognitive Study (ARIC-NCS). These same variants have been previously linked to hypertension and stroke, but their contribution to the loss of cognition with aging is novel. Little is known about the cells that produce 20-HETE or express its newly discovered GPR75 receptor in the brain or the influence of aging and hypertension on the expression of this pathway. 20-HETE inhibitors have been reported to attenuate the myogenic response of cerebral arteries and autoregulation of cerebral blood flow (CBF). Autoregulation of CBF protects the brain from increases in capillary pressure, blood-brain barrier (BBB) leakage, and neurological damage following elevations in blood pressure. Autoregulation of CBF to elevations in pressure is often impaired in elderly, hypertensive, diabetic and AD patients, but its role in the development of cognitive impairment remains to be determined. To validate the association between CYP4A/F mutations and dementia, and to determine the mechanisms involved, Dr Roman?s group identified a homologous genetic deficiency in the formation of 20-HETE in Dahl salt-sensitive (SS) rats, and confirmed they exhibit impaired autoregulation of CBF. They also created transgenic rescue models on the SS genetic background. This project will now test the hypothesis that a genetic deficiency in the formation of 20-HETE, which impairs CBF autoregulation, increases pressure to cerebral capillaries to promote BBB leakage, neurodegeneration, and cognitive dysfunction with aging and/or hypertension. We will identify the cellular localization of the enzymes that produce 20-HETE and its receptors in the brain, and determine if knock-in of the wild-type Cyp4A1 gene in young and elderly SS rats restores the production of 20-HETE and protects against the development of cognitive impairment with aging and/or hypertension. This work has exceedingly high translational value and should lead to the development of genetic tests to identify patients with CYP4A11 and 4F2 mutations that may be at risk for the development of cognitive impairment.
In preliminary studies, we found that sequence variants in the CYP4A11 and 4F2 genes, that reduce the production of 20-HETE, are associated with loss of cognitive function with aging in >4000 elderly patients but the mechanisms involved are unknown. We also identified a homologous genetic deficiency in 20-HETE production in Dahl salt-sensitive rats and confirmed that they also exhibit impaired autoregulation of cerebral blood flow and cognitive dysfunction with aging and hypertension. This proposal will determine the mechanisms by which decreased 20-HETE and impaired cerebral hemodynamics promotes loss of cognitive function with aging and hypertension.