# Hypothalamus-driven anti-aging processes impact murine models of Alzheimer's Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $646,113

## Abstract

This application responds to RFA-AG-20-013 entitled
Worldwide
aging-associated
Approaches to Alzheimer's
increase in life expectancy has produced a dramatic rise in the prevalence, and thus impact of
diseases, including Alzheimer's disease (AD). There is no effective treatment to halt or slow
“Geroscience Disease”.
AD,
and
progress made in the development of new therapies is disappointing since many new compounds,
despite initial promise at the preclinical level, failed in clinical trials (Cummings et al., 2018). The biggest risk
factor for AD is aging. Therefore, novel approaches detecting mechanistic link between aging and AD at the
cellular level, that leads to prodromal neuronal dysfunctions associated with later cognitive impairment and
dementia, core features of AD, are crucial for identifying therapeutic interventions that have potential to modify
course of disease.
Our
precedes
promoting
relevant
the
pharmacological
manifestation
are
Specific
Specific
recent published and preliminary results showed that dyssynchronous activity of neuronal ensembles
onset of symptoms in rat and mouse models of AD. We also identified hypothalamic hunger-
neurons expressing Agouti-related peptide (AgRP) as crucial determinant of systemic metabolism
to calorie restriction, aging and higher brain functions. These observations collectively gave impetus to
central hypothesis of this proposal, which is that suppression of aging by nutrient (calorie restriction) or
(FGF21) interventions will delay t he onse of electrophysiological, behavioral and pathological
of impairments in animal models of AD. We also hypothesize that hypothalamic AgRP neurons
central to the beneficial effects of these interventions. To test these hypotheses, we propose the following
Aims:
Aim 1
t
will test the hypothesis that calorie restriction and FGF21 treatment suppress subclinical and
clinical symptom development and brain pathologies in a transgenic rat model (TgF344-AD) of AD expressing
mutant human amyloid precursor protein (APPswe) and presenilin 1 (PS1ΔE9) genes.
Specific Aim 2 will
of
pathologies
interrogate the hypothesis that hypothalamic AgRP neurons are critical for mediating effects
calorie restriction and FGF21 in modulation of subclinical and clinical symptoms development and brain
in transgenic mouse models (5xFAD and Tg2576) of AD.
To execute these Specific Aims we will utilize rat and mouse models of AD with nutrient and pharmacological
interventions, the combination of in vivo electrophysiology, behavioral analyses, biochemistry and pathological
evaluation of control and experimental animals.
Our studies will directly and forcefully analyze the relationship between aging-related systemic and cellular
processes using electrophysiological (EEG), behavioral, histological and biochemical methods to track
symptoms development of AD in known animal models. The outcome of these studies will immediately suggest
possible interventions to alter AD development in primates, includin...

## Key facts

- **NIH application ID:** 10144367
- **Project number:** 5R01AG067329-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** TAMAS L HORVATH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $646,113
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144367

## Citation

> US National Institutes of Health, RePORTER application 10144367, Hypothalamus-driven anti-aging processes impact murine models of Alzheimer's Disease (5R01AG067329-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144367. Licensed CC0.

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