ABSTRACT Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment which is the second most common cause of dementia after Alzheimer’s disease. There is increasing evidence that blood brain barrier dysfunction and neuroinflammation play a pivotal role in the pathophysiology of hypertension and contribute to the development of vascular cognitive impairment. While Angiotensin II Type 1 receptor antagonists are first line therapy to treat hypertension they have recently been demonstrated to improve neurocognitive function. Given the annual cost of dementia in the US is expected to double by 2040, the prevalence of hypertension rises from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65, and that hypertension incidence increases dramatically post-menopause there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension and vascular cognitive impairment. This application will test the global hypothesis that normal aging evokes sex-dependent hypertension that drives central microvascular injury and neuroinflammation to cause vascular cognitive impairment which can be ameliorated by Angiotensin II Type 1 receptor antagonism. Our Aims will be conducted in male and female 3-, 8-, and 16-month-old Sprague-Dawley rats (model of normal aging). The following Specific Aims will test this hypothesis: Specific Aim 1: Hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to age-dependent hypertension via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2: Age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach is directly aligned with NIA Stratetgic Goals that address Alzheimer's disease and its related dementias and is designed to provide novel insights into the basic mechanisms contributing to sex- and age-dependent hypertension- driven vascular cognitive impairment and fully meets the intent of PAR-19-070 and NOT-AG-20-038. Specific Aim 1 will establish that hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to the development of age-dependent hypertension, which drives vascular cognitive impairment, via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2 will establish that age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach will directly investigate the sex dependent mechanistic sequelae of events and underlying neural dysfunction in both the PVN and hippocampus that is associated with, and perhaps contributing to, age- dependent hypertension-driven vascular cognitive impairment.

PROJECT NARRATIVE Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment, the second most common cause of dementia after Alzheimer’s disease. Given the prevalence of hypertension rises from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65 and that hypertension incidence increases dramatically post-menopause in there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension and vascular cognitive impairment. Our collaborative research strategy, which is directly aligned with NIA Stratetgic Goals that address Alzheimer's disease and its related dementias, will define the sex dependent mechanistic sequelae of events and underlying neural dysfunction that is associated with age-dependent hypertension-driven vascular cognitive impairment and potentially identify new therapeutic targets and approaches for the treatment age-dependent hypertension-driven vascular cognitive impairment.