# RAS-Driven Central Inflammation and Cognitive Decline with Aging.

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2021 · $231,750

## Abstract

PROJECT SUMMARY/ABSTRACT
In the United States, at least five million elderly Americans suffer from dementias, and it is projected that the
number of new dementia cases will double by 2025 due to the growth in life expectancy. Alzheimer’s disease
(AD) is the most common cause of dementia in the elderly and accounts for up to 80% of all dementia
diagnoses. Currently, there is no cure for AD. Thus, there is an urgent need for novel interventions that can
prevent onset and slow the disease progression, thereby improving the quality of life in the elderly.
Apolipoprotein E4 allele (ApoE4) is the most prevalent genetic risk factor for AD and represents 60% of AD
subjects in the general population, yet we do not fully understand how it causes dementia. ApoE protein is
critical for lipid metabolism and cholesterol transport. The other known risk factors for AD include older age,
female gender, and hypertension. Our robust preliminary data obtained from the human ApoE4-knockin (E4)
and ApoE3-knockin (E3) mice, demonstrates that compared to the males, female E4 mice develop cognitive
decline and hypertension with aging. Notably, we find CSF levels of angiotensin II (AngII), the excitatory
component of the brain renin-angiotensin system (RAS), progressively increase with age in the female E4
mice. It is now becoming evident that the proinflammatory actions of AngII damage the blood-brain-barrier and
increase amyloid-b and tau load causing neurotoxicity in spatial learning and memory region of the brain, the
hippocampus (HC). Moreover, AngII acting via type 1 receptors in a cardiovascular region of the brain,
paraventricular nucleus of hypothalamus (PVN), regulates arterial blood pressure and autonomic function.
Thus, our central hypothesis is that brain RAS-driven inflammation mediates cognitive decline and
hypertension in aging, in the ApoE4 genotype. A major concern has been the lack of appropriate murine
models that recapitulate hallmarks of human AD. Hence we will study novel transgenic mice that express the
human ApoE3 or ApoE4 knockin gene combined with three transgenes (APPSW, PS1dE9, and tauP301S) that
model AD in the mice. We will test the novel hypotheses with state-of-the art physiological and molecular
approaches in the following two specific aims.
 Aim 1: To test the hypothesis that brain RAS-induced inflammation drives cognitive impairment in female
 E4 mice.
 Aim 2: To test the hypothesis that hypertension exacerbates cognitive decline in female E4 mice with age.
These studies will define underlying central mechanism(s) of cognitive decline in aging and identify novel
therapeutic target(s) that will enable discoveries from basic science to be translated into clinical practice for
Alzheimer’s disease and related dementias.

## Key facts

- **NIH application ID:** 10301248
- **Project number:** 1R21AG070188-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Rasna Sabharwal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,750
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10301248

## Citation

> US National Institutes of Health, RePORTER application 10301248, RAS-Driven Central Inflammation and Cognitive Decline with Aging. (1R21AG070188-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10301248. Licensed CC0.

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