# Impact of ApoE in Novel Rat Models of Late-Onset AD

> **NIH NIH R21** · UNIVERSITY OF RHODE ISLAND · 2024 · $196,875

## Abstract

Apolipoprotein E4 (ApoE4) is recognized as a strong risk factor for the development of late-onset
Alzheimer’s disease (LOAD). To better understand the impact of ApoE genotype on the emergence and
progression of LOAD and to effectively evaluate therapeutic interventions for this condition appropriate
experimental animal models are needed. To date, most animal model studies designed to address the
contributions of ApoE genotype to AD have largely centered around the use of transgenic mice. Typically, most
transgenic lines for AD rely on highly artificial over-expression of transgenes and largely incorporate one or
more early-onset FAD mutations in AbPP or presenilin. Moreover, transgenic animals are prone to
developmental and insertional effects on the host genome and are susceptible to loss of transgene expression
and genetic drift in subsequent generations. In addition to these caveats, another major shortcoming of
transgenic lines is that any AD pathology that develops typically is from a ‘sole source’ of transgene
expression. In most cases, the ‘sole source’ of transgenic proteins results from strong over-expression in
neuronal cells. With regards to AD, it is known that besides neurons neighboring astrocytes and microglia can
express AbPP, produce Ab peptides and participate in AD pathogenesis. In addition, vascular cell types
including endothelial cells, smooth muscle cells and pericytes all express AbPP, produce Ab peptides and
reside at the site of CAA, a common vascular co-morbidity of LOAD. Since the complexity of the cellular origins
of Ab in AD are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this
disorder and an accurate understanding of the impact of ApoE. This glaring shortcoming has prompted the
quest to generate better experimental animal models for LOAD that more fully capture the pathogenesis of this
condition and more accurately reflect human disease.
 The overall goal of this exploratory proposal is to study the impact of ApoE genotype on the emergence
and progression of LOAD pathologies and cognitive impairment using a novel gene-edited rat model
(CrHuAb) used to generate bigenic CrHuAb/hApoE3 and CrHuAb/hApoE4 rats. These novel and timely rats
will provide superior, state-of-the-art preclinical models that will more realistically reflect the true pathogenesis
of LOAD that develops in patients compared to transgenic mice commonly used in the field.

## Key facts

- **NIH application ID:** 10788858
- **Project number:** 1R21AG085087-01
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** William E. Van Nostrand
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $196,875
- **Award type:** 1
- **Project period:** 2024-02-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788858

## Citation

> US National Institutes of Health, RePORTER application 10788858, Impact of ApoE in Novel Rat Models of Late-Onset AD (1R21AG085087-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10788858. Licensed CC0.

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