# Effects of apolipoprotein E isoform and amifostine on memory-related DNA double strand breaks and immediate-early gene expression

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $28,228

## Abstract

PROJECT SUMMARY
There are many types of DNA damage. Of those, double strand breaks (DSBs) have traditionally been
characterized as the most harmful, as they require a highly complex and easily fallible repair process. DSBs are
caused by a range of harmful factors. When unrepaired, DSBs trigger apoptosis; when repaired incorrectly,
DSBs can lead to tumorigenesis. Increased DSBs are also seen in aging and Alzheimer's disease (AD).
Surprisingly, DSB repair proteins are observed following sub-toxic stimulation in vitro and exposure to a novel
environment in vivo, suggesting a possible adaptive role for DSBs in typical cellular function. The occurrence of
DSBs in the promoter regions of immediate-early genes (IEGs), as well as the increase in repair proteins
observed in anatomically-specific regions after novelty, warrants investigation into this possible adaptive
function. Further, young transgenic mice carrying an AD dominant familial mutation show higher baseline
(“pathological”) levels of DSBs and impaired DSB repair compared to wild-type mice. As familial dominant
mutations only account for ~1% of all AD cases, an increased understanding of the dysregulation of DSBs and/or
IEGs in sporadic AD is greatly needed. The strongest genetic risk factor for sporadic, late-onset AD is
apolipoprotein E (apoE), which exists in 3 major isoforms: E2, E3, and E4. Compared to E3 carriers, E4 carriers
are at a much greater risk to develop AD, while E2 carriers are relatively protected. Alterations in both resting
state and task-associated brain activation are seen in young, non-impaired E4 carriers. Similarly, my preliminary
data show apoE-isoform specific differences in IEG expression following a fear learning task. I will explore how
apoE isoform affects pathological and adaptive DSBs and IEG expression, opening a novel line of investigation
in aging research. There are currently no effective long-term treatments for AD, and new approaches need to be
explored. Many common cancer treatments are designed to decrease pathological DSBs. To assess the
possibility of re-purposing cancer therapies to treat age-associated cognitive decline (ACD) and AD, I propose
to test if a single injection of amifostine, an FDA-approved cancer treatment, increases long-term memory,
decreases pathological DSBs, and/or changes IEG levels. I hypothesize that apoE isoforms differentially
affect pathological and adaptive DSBs and IEG expression. I also hypothesize that amifostine will
decrease pathological DSBs, normalize IEGs, and improve memory in middle-aged E4 mice. In Aim 1, I
will investigate the role of apoE isoform on pathological and adaptive DSBs, DSB repair, and IEGs in middle-
aged female and male mice, providing insight into possible apoE isoform-dependent alterations. In Aim 2, I will
test if a single i.p. injection of amifostine ameliorates apoE-isoform specific memory differences and changes
IEG expression. These experiments will increase our understanding memory-related ...

## Key facts

- **NIH application ID:** 10336373
- **Project number:** 5F31AG067629-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Sydney Jeanne Weber Boutros
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $28,228
- **Award type:** 5
- **Project period:** 2021-02-01 → 2022-06-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336373

## Citation

> US National Institutes of Health, RePORTER application 10336373, Effects of apolipoprotein E isoform and amifostine on memory-related DNA double strand breaks and immediate-early gene expression (5F31AG067629-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10336373. Licensed CC0.

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