# The influence of ApoE4 on signaling & poor outcome after traumatic brain injury

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

## Abstract

This career development award proposal aims to define potential mechanisms that predict outcome after
traumatic brain injury (TBI), while at the same time providing the applicant with training opportunities within the
VA. TBI affects approximately 15% military population. Veterans were subjected to repeated TBI are at increased
risk of developing long-term neurodegenerative disorders. Treatment options are limited, mainly because the
pathology behind neurological deficits due to TBI is poorly understood.
 Apolipoprotein E (ApoE) has several alleles, and patients that express the E4 allele have worse outcomes,
particularly in the long term after TBI. Despite a wide range of studies centered on the ApoE4 allele, none can
be found that investigate the influence of a major ApoE receptor, low density lipoprotein related protein 1 (LRP1),
on outcomes after TBI. Nevertheless, evidence suggests that LRP1 can play a role in modulating TBI outcome-
-LRP1 removes a large variety of cellular proteins, both from the plasma membrane and in the cytosol, and plays
an important role in determining protein expression at the plasma membrane.
 ApoE4 enters cells by binding to LRP1 and undergoing receptor mediated endocytosis. In contrast to other
ApoE alleles (E2, E3), ApoE4 endocytosis and receptor recycling are impaired. In the case of LRP1, impaired
recycling is postulated to greatly alter ability of LRP1 to act as a clearance receptor, therefore changing the milieu
of proteins expressed on the plasma membrane and so altering cellular response to damage. For this proposal,
I am focused on understanding the contribution of LRP1 to TBI pathology in a single cell type, astrocytes. Not
only are astrocytes the primary producers of ApoE in the brain, they also play a tremendous role in determining
outcome by limiting secondary spread of damage after TBI. My working hypothesis is that critical LRP1
function is disrupted by ApoE4 binding in astrocytes, thereby modulating normal cellular responses and
sensitizing the brain to inflammation and cell death after TBI. My research strategy will test this hypothesis
while also providing clear training objectives and career opportunities in order to develop independence.
 Aim 1 tests the hypothesis that loss of astrocyte LRP1 worsens outcome in TBI. Astrocyte-specific LRP1
mice have been generated, and mouse TBI models will test outcome in the acute and chronic outcome. Aim 2
will test the hypothesis that the impact of ApoE4 on TBI outcome depends on LRP1. TBI-like cell culture models
will mechanistically test the influence of ApoE4 and LRP1 on cell survival. One new mouse line will be generated
by crossing ApoE4 targeted replacement mice into the astrocyte-LRP1 knockout model, and then the effect on
outcome after TBI will be tested similar to aim 1. Aim 3 tests the hypothesis that ApoE4 worsens outcome by
increasing signaling through the inflammatory tumor necrosis alpha receptor 1 (TNFR1), elevating cytokine
stimulated cell de...

## Key facts

- **NIH application ID:** 9932269
- **Project number:** 5IK2BX003240-04
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Naomi Ledene Sayre
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932269

## Citation

> US National Institutes of Health, RePORTER application 9932269, The influence of ApoE4 on signaling & poor outcome after traumatic brain injury (5IK2BX003240-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932269. Licensed CC0.

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