# Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2023 · $929,705

## Abstract

PROJECT SUMMARY/ABSTRACT
We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance
to sporadic Alzheimer’s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and
functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic
potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for
Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in
or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number
variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as
pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from
non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined
with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back
into the genome to form “genomic cDNAs” (gencDNAs). These published data contribute to the scientific
foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain-
specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets
for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both
sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR
and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular
neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will
determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes
responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD
via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.

## Key facts

- **NIH application ID:** 10550208
- **Project number:** 5R01AG065541-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** JEROLD CHUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $929,705
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10550208

## Citation

> US National Institutes of Health, RePORTER application 10550208, Altered reverse transcriptase-dependent gene diversification mechanisms in Alzheimer's disease brains (5R01AG065541-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10550208. Licensed CC0.

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