# Dietary sodium, neurovascular dysfunction and cerebrovascular risk

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $599,012

## Abstract

Salt consumption across the world greatly exceeds minimal requirements, and excessive dietary
salt has emerged as a powerful risk factor for cognitive impairment and dementia. Increasing
evidence indicates that a high salt diet (HSD) is harmful to brain health independently of the
increase in blood pressure associated with HSD in salt-sensitive individuals. Unfortunately, public
health efforts to curb salt intake have been futile and dietary salt consumption continues to rise
worldwide. The long-term goal of this research program is to elucidate the mechanisms by which
HSD is injurious to cognitive health and to develop new approaches to counteract it. During the
previous funding period, we have demonstrated that HSD in mice leads to a reduction in cerebral
blood flow (CBF) and cognitive impairment through suppression of endothelial nitric oxide (NO)
production. These effects are mediated by a subclass of T-helper lymphocytes (Th17) in the small
intestine that increases circulating levels of the cytokine IL17. IL17, in turn, leads to inhibition of
endothelial NO synthase (eNOS) in cerebral endothelial cells. The resulting deficit in endothelial
NO induces cognitive impairment through neuronal accumulation of hyperphosphorylated tau, a
microtubule associated protein linked to Alzheimer’s disease and related dementias. However,
the factors triggering the production IL17 in the gut, the cellular localization of the IL17 receptors
inducing eNOS inhibition, and the role of the CBF reduction in tau accumulation remain to be
established. This renewal application seeks to advance the mechanistic understanding of the
cognitive effects of HSD by testing the following novel hypotheses: (a) HSD triggers distinct innate
and adaptive immune responses in the gut through the microbiota, (b) the resulting increase in
circulating IL17 acts on cerebral endothelial IL17 receptors to inhibit eNOS through
downregulation of the eNOS regulatory protein striatin and, (c) the increased leukocyte adhesion
resulting from the NO deficit leads to microvascular occlusions (capillary stalling) which promote
tau accumulation in brain by reducing its microvascular clearance into the bloodstream. We will
use a well-characterized model of HSD in young and old males and female mice and state-of-the-
art approaches to examine gut-brain immune interactions, microvascular function,
hyperphosphorylated tau, and cognitive deficits. These studies advance the understanding of the
pathobiology of excessive dietary salt at the cellular and molecular levels and may lead to new
approaches to mitigate its harmful effects on brain health that lead to cognitive impairment.

## Key facts

- **NIH application ID:** 10298081
- **Project number:** 2R01NS095441-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Costantino Iadecola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,012
- **Award type:** 2
- **Project period:** 2015-12-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298081

## Citation

> US National Institutes of Health, RePORTER application 10298081, Dietary sodium, neurovascular dysfunction and cerebrovascular risk (2R01NS095441-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10298081. Licensed CC0.

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