# Neuroimmune Mechanisms of Cognitive Impairment in Salt-sensitive Hypertension

> **NIH NIH K22** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $132,705

## Abstract

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.

## Key facts

- **NIH application ID:** 10447714
- **Project number:** 5K22NS123507-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Monica M Santisteban Freeman
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $132,705
- **Award type:** 5
- **Project period:** 2021-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447714

## Citation

> US National Institutes of Health, RePORTER application 10447714, Neuroimmune Mechanisms of Cognitive Impairment in Salt-sensitive Hypertension (5K22NS123507-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447714. Licensed CC0.

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