# The Role of Neuronal mTORC1 in Alzheimer's Disease

> **NIH VA IK2** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2020 · —

## Abstract

ABSTRACT
 Alzheimer's disease (AD) affects 1 in 9 people over the age of 65 in the U.S. and is the 6th leading cause of
death in the US. There is no effective treatment for AD. While the number of people affected by AD is expected
to rise rapidly with the increasing age of the U.S. population, our nation's Veteran population is at an even greater
risk for developing AD because of the recent increase in combat-related injuries such as traumatic brain injury
and posttraumatic stress disorder, both of which are significant risk factors for AD. Recent studies from our and
others' laboratories showed that attenuation of the mechanistic target of rapamycin (mTOR) with rapamycin halts
the progression of AD-like memory deficits in several different mouse models of AD even when treatment is
started after the onset of AD-like cognitive deficits, effectively `stopping' the progression of the disease until the
end of lifespan. Systemic rapamycin ameliorates learning and memory deficits, decreases brain amyloid β levels
by increasing autophagy, and restores brain vascular function and integrity in AD mice. The specific contribution
of neuronal versus vascular mechanisms in the restoration of memory in AD mice by attenuation of mTORC1,
the main target of rapamycin, however, is still unknown. The present research proposal will define the
contribution of neuron-driven mTORC1-dependent mechanisms to the pathogenesis of AD by genetically
knocking down mTORC1 specifically in neurons of adult AD-model mice. The proposed research is innovative
because it focuses on the contribution of mTORC1-driven mechanisms acting specifically in neurons, that will
be examined using a uniquely novel neuronal-specific adult mTORC1 knockdown mouse model of AD; and is
significant, as it will lead to a better understanding of AD pathogenesis and will identify novel targets for clinical
interventions. With the aims of this proposal, I will test the hypothesis that reducing mTORC1 specifically in
neurons will ameliorate AD-like cognitive deficits in AD mice (Aim 1) by increasing autophagy at the synapse
and improving synaptic function (Aim 2), and by improving brain vascular health (Aim 3).
 If my studies support this hypothesis, my work is expected to have a positive impact on Veteran's health
because it will lead to the development of targeted pharmacological strategies to treat AD, including but not
limited to drugs that are currently FDA-approved for clinical use. Thus my findings could be rapidly translated to
treatments for AD. In addition, my studies will reveal the mechanisms by which attenuating mTORC1 in neurons
contributes to halting the progression of AD-like disease in mice, and thus will significantly advance our
understanding of the pathogenesis of AD. By performing the proposed research, I will obtain training in key
experimental approaches as well as gain critical experience in various aspects of professional development.
This training will significantly advance my resea...

## Key facts

- **NIH application ID:** 9898230
- **Project number:** 5IK2BX003798-03
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** STACY A. HUSSONG
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898230

## Citation

> US National Institutes of Health, RePORTER application 9898230, The Role of Neuronal mTORC1 in Alzheimer's Disease (5IK2BX003798-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898230. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*