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 disturbances and begin assessing a novel treatment approach. This project serves as a critical and novel first step in understanding the role of DSBs in apoE-isoform specific risks for ACD and AD, and possible future treatment options.

Public Health Relevance

DNA double strand breaks (DSBs) have classically been thought of as a harmful result of injury or insult, but recent evidence from both our lab and others suggests a previously unheard-of idea that DSBs might also play an adaptive role by moderating immediate-early gene (IEG) expression, which is necessary for learning and memory formation. As DNA damage is known to increase in aging and disease states, I will explore how isoforms of apolipoprotein E (apoE), that differ in risk to develop age-related cognitive decline and late-onset Alzheimer's disease, differentially regulate the formation and repair of DSBs and IEG expression. Further, I propose to test the ability of amifostine, a common cancer therapy which increases the speed of DSB repair, to improve fear memory in middle-aged apoE mice and whether this effect is associated with altered IEG expression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dibattista, Amanda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
Zip Code