PROJECT SUMMARY Dementia is a major cause of death and disability and has emerged as one of the major public health issues of today. Hypertension is a leading risk factor for dementia, both Alzheimer disease (AD) but also Alzheimer disease related dementias (ADRD). Hypertension disrupts the function of the neurovascular unit and promotes vascular insufficiency, leading to neuronal dysfunction and cognitive impairment. Salt-sensitivity is a critical factor in essential hypertension, affecting approximately 50% of hypertensive individuals, but it is unknown how it leads to cognitive impairment. Dietary salt activates signaling pathways which promote production of interleukin-17 (IL17), and increasing circulating levels of the cytokine IL17 have been identified in patients with hypertension, raising the possibility that this cytokine may be involved. Here we will test the hypothesis that the harmful effects of salt-sensitive HTN are mediated by IL17 acting on IL17 receptors on both endothelial cells and perivascular macrophages (PVM), free radical-producing immune cells located in the perivascular space closely apposed to cerebral microvessels, via two distinct mechanisms: (1) circulating IL17 acts on endothelial cells to induce a loss of the beneficial effects of nitric oxide (NO), while (2) T-cells infiltrating the meninges increase IL17 in the cerebrospinal fluid which acts on PVM to induce oxidative stress and proinflammatory signaling. Together, these actions lead to cerebrovascular dysfunction and cognitive impairment in salt-sensitive HTN. To this end, we will first establish the temporal relationship between neurovascular and cognitive dysfunction in a mouse model of salt-sensitive hypertension. Then, we will use pharmacological and cell-specific genetic approaches to determine the contribution of IL17 to the neurovascular and cognitive dysfunction in this model, and establish what are the cellular targets of IL17 in the neurovascular unit. Finally, we will determine the role of peripheral versus central T-cells in mediating the dysfunction, focusing on the relative contribution of meningeal IL17gdT-cells. To achieve these goals, we will use state-of-the-art approaches to study neurovascular regulation, including genetic models for specific conditional knockdown of the IL17 receptor subunit A. In addition to providing me with a unique training opportunity, these studies will fill an obvious gap in the understanding of the mechanisms by which HTN and excessive dietary salt lead to cognitive impairment and may provide new therapeutic approaches to mitigate the damaging effects of HTN on cognitive health.