# Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system.

> **NIH NIH P01** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $465,497

## Abstract

Project 1 Summary
Basic and pre-clinical research provides convincing evidence that estrogens exert neuroprotective effects in
the hippocampus, a brain area critical for memory and vulnerable to effects of aging and Alzheimer’s disease.
Thus, expectations were that menopausal hormone therapy would be neuroprotective and decrease the risk of
Alzheimer’s disease and related dementias in women. However, the benefits of hormone therapy on the brain
and cognition are unresolved. Whereas preclinical research is primarily conducted in models of healthy aging,
clinical research often includes subjects with diverse health status. To reconcile this evidence gap, we will
determine impacts of cardiometabolic status on the ability of estrogens to beneficially impact the hippocampal
memory system. Our central hypothesis is that in aging females, cardiometabolic disease, due to associated
dysfunction of the ubiquitin/proteasome system, disrupts the ability of estrogens to regulate levels of ERα in
the hippocampus, regulation that is necessary for estradiol treatment to exert lasting positive effects on
memory during aging. The hypothesis will be tested by the following specific aims: 1) determine if individual
differences in the response to midlife estradiol treatment on the hippocampal memory system are associated
with individual differences in cardiometabolic health; 2) determine if estradiol effects on the hippocampal
memory system in aging females are impacted by obesity and impaired glucose regulation; and 3) determine if
estradiol effects on the hippocampal memory system in aging females are impacted by cardiovascular disease.
Experiments under the first aim will use a longitudinal study design and a rat model of midlife estradiol use—in
which estradiol is administered either immediately after the cessation of ovarian function or after a delay—to
assess relationships between measures of body fat accumulation, glucose regulation, cardiovascular function,
hippocampal function, and memory from middle to old age. Experiments under the second aim will expose
middle-aged female rats to a high-fat or control diet before or after the initiation of midlife estradiol treatment
and a) assess the ability of midlife estradiol to exert effects on levels of hippocampal ERα, measures of
hippocampal function, and memory; and b) determine if increasing levels of hippocampal ERα differentially
affect memory and the hippocampus in aging females on high-fat or control diets. Experiments under the third
aim will use an angiotensin II-dependent hypertensive rat model to a) assess the ability of midlife estradiol to
exert effects on levels of hippocampal ERα, measures of hippocampal function, and memory; and b) determine
if increasing levels of hippocampal ERα differentially affect memory and the hippocampus in aging females
without or without hypertension. Results will determine under which conditions estrogen treatment provides
beneficial effects to the hippocampally mediated ...

## Key facts

- **NIH application ID:** 10334232
- **Project number:** 1P01AG071746-01A1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** JILL M DANIEL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $465,497
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334232

## Citation

> US National Institutes of Health, RePORTER application 10334232, Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system. (1P01AG071746-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10334232. Licensed CC0.

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