# Assessing impaired neuroinflammation associated with Apolipoprotein E4

> **NIH NIH F31** · UNIVERSITY OF KENTUCKY · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT:
Alzheimer’s Disease (AD) remains the leading cause of dementia worldwide and 6th leading cause of death in
the United States. While the majority of AD cases have no clear genetic cause, a few genetic risk factors for
developing AD have been identified. One of the most significant genetic risk factors is Apolipoprotein E (ApoE).
Of the three identified ApoE isoforms, ApoE4 confers an increased risk of AD, ApoE3 is believed to be the
“control” phenotype, and ApoE2 has been shown to be protective for AD. Interestingly, ApoE has been shown
to interact with a surface receptor on microglia, triggering receptor expressed on myeloid cells 2 (TREM2) which
has also been shown to confer an increased risk of AD. Recent studies suggest this interaction drives microglial
gene expression and function toward an activated microglial state in the presence of neurodegeneration,
suggesting a role for ApoE in the inflammatory response seen in AD. While the AD field has established ApoE
and TREM2 as risk factors for AD, the mechanistic insights into these risk factors remain murky at best.
Preliminary results for this project, using autopsy tissue from the University of Kentucky– Alzheimer’s Disease
Center Brain Bank, suggests ApoE3 patients with AD have a neuroinflammatory response differing from that
seen in ApoE3 patients without AD, suggesting that the ApoE3 isoform is responding to AD pathology. In
contrast, ApoE4 patients with AD tend to be in a state of neuroinflammation similar to that found in ApoE3
patients without AD, suggesting they cannot respond to the AD pathology. This project aims to determine the
impact of ApoE isoforms on the inflammatory cascade in both mouse and human models. We hypothesize
that the ApoE4 isoform impairs a beneficial neuroinflammatory response in AD and has a weakened interaction
with TREM2. To delve into the differences highlighted by the preliminary data, two approaches will be used to
determine the impact of the ApoE isoform dependent mechanism. First, we will continue investigating the
neuroinflammatory profile of AD autopsy brains by determining microglial morphology in ApoE3/3 and ApoE4/4
patients with AD to compare activation states of the microglia. We will also perform NanoString Digital Spatial
Profiling to look at proteins surrounding AD hallmarks and microglia. These approaches will allow for a deeper
understanding of how these changes seen from the preliminary data associate with the pathology. Our second
approach will use animal models to target TREM2 and investigate the impact ApoE isoforms have on TREM2
activation. We will target TREM2 activation using phosphatidylserine and a TREM2 agonizing antibody to allow
for a more comprehensive view of the impact ApoE isoforms have on TREM2 activation. This project overall
aims to investigate the importance of ApoE isoforms on neuroinflammation to in an ApoE isoform specific
manner. Cumulatively, this proposal provides adequate time and with excelle...

## Key facts

- **NIH application ID:** 10065871
- **Project number:** 1F31AG069372-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Courtney Marie Kloske
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065871

## Citation

> US National Institutes of Health, RePORTER application 10065871, Assessing impaired neuroinflammation associated with Apolipoprotein E4 (1F31AG069372-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065871. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*