# Tissue-specific modulation of Apolipoprotein E in neurodegeneration

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $30,499

## Abstract

PROJECT SUMMARY:
Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) are multifaceted, progressive
neurodegenerative conditions that place a monumental burden on patients, providers, and the public
healthcare system. No disease-modifying treatments are currently available for either AD or ALS. Although the
etiology of each disease is well studied, strategies targeting characteristic features of disease pathogenesis—
e.g., beta-amyloid in AD—show limited clinical efficacy. Identification of novel targets that modify progression
of neurodegeneration is needed for innovative therapeutic development across neurodegenerative disorders.
AD and ALS are caused by genetic and environmental factors that alter downstream pathways like lipid
homeostasis. A critical player in systemic and central nervous system (CNS) lipid transport, that is also
implicated in the onset and progression of neurodegeneration, is apolipoprotein E (ApoE). Genetic deletion of
ApoE reduces neuropathology in mice, but also causes atherosclerosis. Thus, despite its implication in
disease, the diverse functionality of ApoE in its distinct biological “pools” (i.e. systemic and CNS) makes it a
challenging therapeutic target. Reducing individual ApoE pools may circumvent this issue. However, the
independent effects of systemic or CNS ApoE silencing on neurodegenerative diseases are unclear.
The goal of this proposal is to determine the relationship between systemic and CNS ApoE pools, and their
effects on disease progression in AD and ALS mice. The project will take advantage of chemically-stable, self-
delivering small interfering RNAs (siRNAs) that enable sustained, tissue-specific silencing of target mRNA.
GalNAc-siRNAs specifically deliver to liver (site of systemic ApoE production), and divalent (Di)-siRNAs deliver
throughout the brain and spinal cord after intra-cerebroventricular (ICV) injection.
With guidance from Drs. Anastasia Khvorova (siRNA chemistry), Robert Brown (ALS), Evgeny Rogaev (AD
models), Andrew Tapper (animal behavior), and Thomas Smith (neuropathologist), GalNAc- and Di-siRNA will
be used to silence hepatic and CNS ApoE, respectively, and the effects on CNS and systemic ApoE pools, and
AD and ALS phenotypes, will be examined. In Aim 1, GalNAc-siRNA targeting ApoE will be subcutaneously
injected into mice. In Aim 2, Di-siRNA targeting ApoE will be delivered to the CNS via ICV injection. Both aims
will utilize the APP/PSEN1 mouse model of AD and the SOD1G93A mouse model of ALS, and will measure
systemic and CNS ApoE and cholesterol levels, and AD and ALS neuropathology and behavior two months
post injection. These studies will advance the understanding of how ApoE pools interact in the context of
neurodegeneration, and the effects on disease progression. Such findings will inform strategies for safe and
effective therapeutic targeting of ApoE in AD, ALS, and age-related neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10020164
- **Project number:** 5F30AG066373-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Chantal Ferguson
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,499
- **Award type:** 5
- **Project period:** 2019-09-10 → 2023-09-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020164

## Citation

> US National Institutes of Health, RePORTER application 10020164, Tissue-specific modulation of Apolipoprotein E in neurodegeneration (5F30AG066373-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10020164. Licensed CC0.

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