# Sleep disruption in the progression and treatment of Alzheimer's disease

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $33,614

## Abstract

Project Summary
Sleep is an essential physiological behavior that supports cognitive function. In Alzheimer's disease (AD), a
devastating neurodegenerative disorder, patients experience accelerated sleep loss which can be correlated
with AD onset and contribute to AD progression. Tau is an axonal microtubule stabilizing protein that forms
aggregates and contributes to the cognitive decline, synapse loss and neuronal death seen in AD. Recently, Tau
has been shown to mislocalize and aggregate in synapses which may impair synapse weakening during sleep
– likely responsible for forming the restorative benefits of sleep. Currently there are no therapies to alleviate the
negative consequences of tau pathology in AD. Endocannabinoids provide an intriguing avenue for therapeutic
intervention because of their role in promoting antinflammatory signaling and sleep. Therefore, the objectives of
this proposal are to test the link between sleep disruption and tau aggregation and to test the therapeutic window
targeting endocannabinoid signaling during sleep in advance of Tau pathology and cognitive decline. I
hypothesize that sleep disruption occurs early in AD progression and is a major driver of subsequent tau
mislocalization and aggregation, and cognitive decline. In order to test this hypothesis, I have obtained P301S
(PS19) transgenic mice that overexpress aggregation-prone human Tau. These animals show age-dependent
cognitive decline and Tau accumulation. In Aim 1, I will monitor sleep in 6 months PS19 and WT animals and
correlate the appearance of sleep disruption with Tau pathology, in order to link sleep disruption and synaptic
Tau pathology. Additionally, I will subject mice to chronic sleep disruption via a fragmented sleep paradigm to
correlate sleep disruption with Tau pathology. Using various biochemical assays, I will identify sleep-dependent
changes at the mRNA and protein level. In Aim 2 I will generate FAAH-/-/PS19 mice and define sleep phenotypes
in males and females. I will determine whether genetic regulation of synaptic eCBs can improve sleep in PS19
mice and reduce tau pathology at 6 months. Additionally, I will test the lasting effects of genetic manipulation of
eCBs on sleep quantity and quality through a battery of cognitive tests. Synaptic sleep-dependent changes will
be identified through biochemical assays. These studies will provide a deeper understanding of the behavioral
and molecular changes that occur during abnormal sleep in AD and highlight endocannabinoids as a suitable
signaling pathway for enhancing the restorative benefits of sleep. This proposal combines behavior,
biochemistry, pharmacology and molecular biology to provide outstanding training opportunities for my scientific
development and future career in biomedical science.

## Key facts

- **NIH application ID:** 10474344
- **Project number:** 5F31AG074649-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Shenee Martin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,614
- **Award type:** 5
- **Project period:** 2021-08-03 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474344

## Citation

> US National Institutes of Health, RePORTER application 10474344, Sleep disruption in the progression and treatment of Alzheimer's disease (5F31AG074649-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10474344. Licensed CC0.

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