# The role of post-traumatic sleep-wake disruption in the development of tau pathology following mild traumatic brain injury

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

PROJECT SUMMARY
Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of
neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy, which are
characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to
tau pathology later in life remain unknown.
The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the
rapid exchange of cerebrospinal and interstitial fluid. Glymphatic function contributes to the clearance of both
amyloid beta and tau, and its impairment is believed to underlie their deposition in the aging brain. Glymphatic
pathway function is greatest during sleep and is impaired by traumatic brain injury. Based on these findings,
we hypothesize that that impairment of glymphatic function following mTBI slows the clearance of tau and
contributes to the development of tau pathology following injury. Using a well-established model of repetitive-
blast mTBI, behavioral assessment of cognitive and functional impairment, and histological assessment of tau
pathology in a rodent model of tauopathy, we will characterize glymphatic dysfunction following blast mTBI,
and test whether its impairment promotes post-traumatic tauopathy.
Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI. SWD also accompanies
the development of conditions like Alzheimer's disease in aging populations. More recent clinical and
translational research suggests that SWD may actually promote the development of Alzheimer's-related
pathology, including tau deposition. Based on the common clinical connections between mTBI, SWD, and
neurodegenerative disease, we hypothesize that post-traumatic SWD contributes to the development of
tauopathy following mTBI. Using parallel techniques above, we will define SWD following blast mTBI, and test
whether post-traumatic SWD promotes the development of tau pathology after injury.
In both observational clinical studies and in rodent models, post-concussive symptoms exhibit different
temporal profiles following single or repetitive mTBI. To comprehensively define the role that glymphatic
impairment and sleep disruption play in the development of tau pathology following mTBI, these studies will be
carried out in parallel in mouse models of single and repetitive blast mTBI.
The results of this study may provide a novel perspective on the mechanisms underlying the development of
post-traumatic neurodegeneration, and may support targeting glymphatic pathway function and SWD in the
prevention and treatment of conditions such as Alzheimer's disease in Veteran populations with a history of
exposure to mTBI.

## Key facts

- **NIH application ID:** 10844381
- **Project number:** 5I01BX005735-02
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Jeffrey J Iliff
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844381

## Citation

> US National Institutes of Health, RePORTER application 10844381, The role of post-traumatic sleep-wake disruption in the development of tau pathology following mild traumatic brain injury (5I01BX005735-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10844381. Licensed CC0.

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