# Characterizing sleep disruption as a post-injury immune stressor

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $255,967

## Abstract

Project Summary/Abstract
Epidemiological evidence points to a relationship between traumatic brain injury (TBI) and Alzheimer’s disease;
however, many experimental studies fail to show this, with some even reporting a reduction in Alzheimer’s-like
pathology over time. Most of these studies utilize mouse models with genetic mutations associated with early
onset Alzheimer’s disease. This strategy largely ignores the relationship between TBI and development of late-
onset Alzheimer’s disease (LOAD), which is much more prevalent in clinical populations. As a result there is a
gap in defining biological pathways linking TBI and LOAD. Here, we propose to define the response to TBI in a
novel mouse model of Alzheimer’s disease created by the Model Organism Development & Evaluation for Late-
Onset Alzheimer’s Disease (MODEL-AD) consortium that became available in 2019- APOE4/Trem2*R47H.
APOEϵ4 and Trem2*R47H are closely linked to immune signalizing in the brain and highly associated with
development of LOAD. Moreover, recent evidence suggests that TREM2 binds to APOE and that the TREM2
R47H variant reduces this affinity. Indeed, Aβ clearance is more efficient for TREM2 and microglia when it is
bound to APOE, and TREM2-deficient microglia show impaired uptake of Aβ. Together, these data suggest that
APOE and TREM2 may influence LOAD through inflammation and impaired debris clearance. This process may
be critical in linking TBI to Alzheimer’s disease as well. We hypothesize that TREM2*R47H will directly affect the
microglial response to TBI and promote the appearance of Alzheimer’s disease-like pathology in humanized
APOE4 mice. In Aim 1, we will define the neuropsychiatric, neuroinflammatory, and neuropathological effects of
TBI or sham injury in APOE4/Trem2*R47H mice at 7, 30, and 120 days post-injury (DPI). In Aim 2, we will
delineate changes in whole brain as well as microglia specific transcriptome with RNA sequencing at 7 and 30
DPI in APOE4/Trem2*R47H mice. These studies build on our expertise in TBI and neuroinflammation, and
provide an opportunity to examine the relationship between TBI and Alzheimer’s disease in a clinically relevant
model. Upon conclusion, we will have a detailed phenotypic characterization of APOE4/Trem2*R47H mice in
response to TBI and identify microglia specific transcriptome changes that may substantially influence chronic
recovery. These data will be essential in future proposals aiming to improve outcome after TBI.

## Key facts

- **NIH application ID:** 10123739
- **Project number:** 3R01NS109585-02S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Olga N. Kokiko-Cochran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,967
- **Award type:** 3
- **Project period:** 2020-08-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123739

## Citation

> US National Institutes of Health, RePORTER application 10123739, Characterizing sleep disruption as a post-injury immune stressor (3R01NS109585-02S1). Retrieved via AI Analytics 2026-07-15 from https://api.ai-analytics.org/grant/nih/10123739. Licensed CC0.

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