# Determining the mechanisms of the protective APOE3ch variant on Alzheimer's Disease pathologies

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $43,471

## Abstract

Project Summary
Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is the most common cause of
dementia among older adults, 65 years and older. AD is characterized by the presence of extracellular amyloid
β plaques (Aβ), intracellular neurofibrillary tau tangles (NFTs), and brain-wide neuroinflammation. Many current
therapeutics targeting either Aβ or tau development have not been successful; therefore, it is imperative to
understand the mechanisms in which these pathological hallmarks interact and influence each other. Aβ plaques
develop many years before disease onset and do not correlate with clinical symptoms like the spread of tau.
Moreover, immunotherapy targeting amyloid has failed to show cognitive improvement despite the significant
reduction in Aβ load. While NFT-like tau pathology can develop without the presence of Aβ, the introduction of
Aβ fibrils significantly accelerates NFT formation, further highlighting the need to better understand their
molecular interactions. Recently, a case study has identified a carrier of the familial AD PSEN1 E280A mutation
with a rare mutation in APOE3 (APOE R136S or APOE3ch) that resulted in resistance to neurodegeneration
along with reduced NFTs while still exhibiting an elevated amyloid plaque load in the brain. The R136S mutation
is located in a region of APOE known to have a role in binding to lipoprotein receptors and heparan sulfate
proteoglycan (HSPGs), which have been suggested to promote amyloid-β aggregation and neuronal uptake of
extracellular tau. Therefore, the APOE3ch mutation provides a unique interface to study the interaction between
Aβ and tau. To that end, we have developed a novel ApoEch mouse model to be crossed with two different
mouse models of amyloid and tau, 5xFAD and PS19, respectively. Thus, I propose to 1) Examine the protective
effect of the ApoEch mutation in reducing tau pathology and rescuing neurodegeneration in PS19 mice, and 2)
Assess the protective effect of the ApoEch mutation in dampening Aβ-associated plaque pathology and
inflammation in 5xFAD mice. Collectively, this proposal will elucidate the role of this unique mutation in the
development and manifestation of both Aβ and tau pathologies in mice.

## Key facts

- **NIH application ID:** 10750905
- **Project number:** 1F31AG084190-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Kristine Minh Tran
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $43,471
- **Award type:** 1
- **Project period:** 2023-08-10 → 2025-08-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750905

## Citation

> US National Institutes of Health, RePORTER application 10750905, Determining the mechanisms of the protective APOE3ch variant on Alzheimer's Disease pathologies (1F31AG084190-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10750905. Licensed CC0.

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