# Sex Specific Acceleration of Pathological Aging After AIE

> **NIH NIH P50** · STATE UNIVERSITY OF NY,BINGHAMTON · 2024 · $266,056

## Abstract

PROJECT SUMMARY
MAIN 2
Excessive alcohol use can increase the risk of alcohol-related brain damage and cognitive decline, including
an increased risk for the development of dementia. Converging data from human studies and preclinical animal
models have revealed that extreme alcohol binge drinking/exposure during adolescence is associated with
long-term changes in brain structure and connectivity. Persistent brain damage after adolescent intermittent
ethanol exposure (AIE) in rodents, a model of binge drinking, entails reduced hippocampal neurogenesis,
suppression of the cholinergic neuronal phenotype, and alterations in the ratio between pro and mature
neurotrophins. This brain profile is also seen in patients with Alzheimer’s Disease and Related Dementias
(ADRD), as well as in preclinical models of such disorders. Subclinical neuropathology and/or alteration in
neurotrophins following AIE likely makes the brain more vulnerable to the aging process, and normal
compensatory aging responses may fail, leading to the behavioral sequelae of dementia. The goal of this
proposal is to reveal how intermittent alcohol exposure during adolescence alters the normal age-related
trajectory (loss of cholinergic phenotype, reduced neurogenesis) in the F344 rat, as well as the onset of
additional AD-pathological markers (plaque load, hyper tau phosphorylation,) in the TgF344-AD model.
Specifically, we will (a) reveal AIE-induced sex-specific neurotrophic mediators of resilience and susceptibility
to compromised cognitive aging and AD-related pathology (AIM 1); (b) rescue sex-specific AIE-induced
acceleration of pathological age-related cognitive decline and AD pathology by inhibiting the p75NTR cell death
pathway (AIM 2). Finally,
we will determine if exercise load drives the sex-dependent recovery of
AIE/AD-associated spatial memory impairment and neuropathology
(AIM 3). Our preliminary data revealed a
profile that AIE accelerates age-related cognitive impairment in male rats, and amplifies pathological aging in
female rats with AD transgenes. Ultimately, this proposal will d
etermine the sex-specific drivers of accelerated
age-related pathology associated with alcohol use disorders to inform effective therapeutic approaches to halt
the progressive development of dementia.

## Key facts

- **NIH application ID:** 10740448
- **Project number:** 2P50AA017823-16
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** Lisa M Savage
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $266,056
- **Award type:** 2
- **Project period:** 2009-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740448

## Citation

> US National Institutes of Health, RePORTER application 10740448, Sex Specific Acceleration of Pathological Aging After AIE (2P50AA017823-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10740448. Licensed CC0.

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