# Mechanisms underlying DNA double strand break response in Alzheimer?s disease and frontal temporal dementia

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $401,374

## Abstract

DNA damage perturbs genomic stability and has been linked to age-associated cognitive decline, as well as to
early stages of various neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral
sclerosis, and frontotemporal dementia (FTD). However, our mechanistic understanding of how DNA damage
contributes to neuronal vulnerability and deterioration remains an unresolved, yet extremely important
question. A major confounding factor is that the sources of damage that are most pertinent to
neurodegeneration remain unknown and the precise mechanisms that connect genomic instability to
neurodegeneration are poorly understood. In addition, it is unclear whether the deterioration of brain function
results solely from a random accumulation of DNA damage throughout the genome, or whether there are
“hotspots” of damage that mediate this process. The goal of our research is to better understand the
mechanisms underlying genomic instability in neurodegeneration and identify novel therapeutic targets to
dampen this early pathological hallmark of neuronal vulnerability. We hypothesize that genomic instability is a
major underlying mechanism of cognitive decline and neuronal vulnerability in AD and FTD. Towards testing
this hypothesis, our specific aims are: 1) to identify genomic loci that are vulnerable to the accumulation of
DNA damage, particularly DNA double strand breaks (DSBs) in mouse and human induced pluripotent cell
(iPSC)-derived models of AD and FTD, 2) to determine the precise defects in DSB signaling/repair in mouse
and human iPSC-derived models of AD and FTD, and 3) to identify modifiers that reduce DNA damage
susceptibility in iPSC-derived neural cells from patients with familial AD and FTD using a novel high-throughput
screening strategy. Our preliminary findings suggest that excessive DNA DSBs are an early pathological
hallmark of neurodegeneration that can be modeled in both mouse and human systems. Obtaining increased
mechanistic insight into the failure to respond to and/or repair DNA DSBs in the context of neurodegenerative
mutations will broaden our understanding of how genomic instability contributes to decline in brain health and
cognition, and provide novel avenues for early therapeutic intervention in neurodegeneration.

## Key facts

- **NIH application ID:** 10210448
- **Project number:** 5R01NS102730-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Li-Huei Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,374
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210448

## Citation

> US National Institutes of Health, RePORTER application 10210448, Mechanisms underlying DNA double strand break response in Alzheimer?s disease and frontal temporal dementia (5R01NS102730-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10210448. Licensed CC0.

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