# Ventral tegmental area involvement in Alzheimer's pathology

> **NIH NIH R21** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $480,700

## Abstract

Alzheimer's disease (AD) is most commonly diagnosed subsequent to memory deficits, but co-morbidities
include a slew of cognitive and non-cognitive impairments including depression, apathy, and movement
disorders. While most work on AD has thus far focused on effects in the cortex and hippocampus, the
pathophysiology associated with AD is found throughout the brain, and many of the secondary symptoms
suggest involvement of the midbrain dopaminergic system. A recent major study as well as preliminary data
suggest that dopamine neurons of the ventral tegmental area (VTA) may be affected in mouse models of AD
prior to the formation of amyloid plaques and neurofibrillary tangles, suggesting a possible role for the VTA in
the prodromal phase of the disease. This field is currently limited by the lack of information on the structural
and functional deficits that develop in single dopamine neurons in the early stages of AD, as well as
their relationship with decrements in hedonic and reward learning behavior. The experiments in this proposal
will focus on two established mouse models of AD. APP/PS1 mice express a mutated human amyloid
precursor protein and a deletion of presenilin 1, while triple transgenic 3xTg-AD mice also express a transgene
for a human mutant tau. The general strategy will be to measure deficits in dopamine-mediated behavior
(sucrose preference, an operant learning task, and locomotor assays) in mutant mice aged 3, 6, and 10
months, and non-transgenic controls, followed by sacrifice for electrophysiology and RNA sequencing of single
VTA dopamine neurons. Aim 1 will focus on both intrinsic and synaptic conductances that affect dopamine
neuron firing and have been identified in preliminary studies as possibly being affected in AD. Aim 2 will test if
a commonly used anti-aging intervention, dietary restriction, can mitigate some or all decrements in ion
channel physiology, behavior, and neuronal morphology. As the prevalence of ADRD continues to increase,
we are in desperate need of AD treatments that not merely alleviate symptoms but slow or halt the progression
of the disease. These treatments do not currently exist because we lack a fundamental understanding of the
decrements in cellular and circuit function that occur during the early stages of pathology. The work in this
proposal will advance the field toward better treatments by establishing the involvement of dopaminergic
processes in AD mouse models. Delineating the sequence of pathological events will allow for the identification
of molecular targets for intervention in early AD.

## Key facts

- **NIH application ID:** 10235590
- **Project number:** 1R21AG072811-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Michael J Beckstead
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,700
- **Award type:** 1
- **Project period:** 2021-05-15 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235590

## Citation

> US National Institutes of Health, RePORTER application 10235590, Ventral tegmental area involvement in Alzheimer's pathology (1R21AG072811-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10235590. Licensed CC0.

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