# Vascular cognitive impairment in hypertension; identification of an age appropriate model.

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2021 · $195,625

## Abstract

Abstract
The number of patients suffering from dementia is expected to reach epidemic proportions within 30 years.
Cerebrovascular disease leads to the development of a specific spectrum of cognitive disorders that range from
mild vascular cognitive impairment (VCI) to life altering vascular dementia (VaD). VaD is the second most
common type of dementia following Alzheimer’s disease (AD). VaD exists lone in 5-10% of dementia cases, but
more commonly appears with, and exacerbates, other dementias including AD. This presents the possibility that
the cerebral vasculature is a therapeutic target to slow or stop the development of dementia. Functional cerebral
arteries are crucial for nutrient and oxygen delivery, and they could also serve as a conduit for
neuroprotective/restorative drug delivery. Any potential dementia treatment will need to undergo preclinical
testing in appropriate animal models but the availability of models for VaD is surprisingly limited; the studies
proposed will fill this knowledge gap. Strong evidence links midlife hypertension to dementia development later
in life. This connection is likely the result of hypertension associated impairments in vascular function and chronic
cerebral hypoperfusion. Many signaling pathways have been identified as mediators of the effects of
hypertension on cerebral arteries. It is not clear how well these pathways translate to humans because most
studies utilized young animals; these models do not account for the combined effects of hypertension and aging.
To identify and validate therapeutic targets it is vital that we model that disease progression appropriately; this
requires that hypertension does not begin until middle-age. A new model of hypertension has been developed
that could be used to recapitulate the time course of hypertension development in the population. In this model,
designer receptors exclusively activated by designer drugs (DREADDs) are utilized to induce
hyperaldosteronism and hypertension. The AS+/Cre hM3Dq mice express the Gq-coupled DREADD specifically in
the adrenal cortex, where receptor activation induces aldosterone synthase expression resulting in primary
hyperaldosteronism. Our central hypothesis is that the AS+/Cre hM3Dq mice will be a useful model VCI/VaD that
appropriately reflects the aging population and their dementia related co-morbidities. In aim 1 we will evaluate
the development of hypertension in AS+/Cre hM3Dq mice when DREADD activation with clozapine N-oxide (CNO)
is delayed until middle-age. Aims 2 and 3 will utilize behavioral testing and molecular methods to assess cognitive
function. We know that aging and hypertension individually impair cerebral artery function; we do not know if the
two conditions have an additive effect. The proposed studies will provide the field with a viable model for
preclinical testing of potential therapies for VaD. This model will also allow for the elucidation of the mechanisms
linking hypertension to cerebral small ve...

## Key facts

- **NIH application ID:** 10313508
- **Project number:** 1R21AG074514-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** ANNE M. DORRANCE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,625
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313508

## Citation

> US National Institutes of Health, RePORTER application 10313508, Vascular cognitive impairment in hypertension; identification of an age appropriate model. (1R21AG074514-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313508. Licensed CC0.

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