# Comparative Single-Cell Epigenomic Analysis of AD-like Pathogenesis in Unconventional Animal Models

> **NIH NIH R24** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $1,188,746

## Abstract

Project Summary / Abstract
 Alzheimer's disease (AD) is the most common cause of human dementia that progressively worsens with
age. Sporadic late-onset AD accounts for more than 90 percent of Alzheimer’s cases without clear documented
familial history of the disease. However, the vast majority of existing transgenic and knock-in models incorporate
disease-causing familial mutations in one or more genes associated with dementias, representing a major
limitation. The RFA-AG-21-003 [New/Unconventional Animal Models of Alzheimer’s Disease] highlights the
need to develop and characterize naturally occurring “non-murine models of AD that may represent improved
translational potential by better replicating pathological features of the human disease”. We respond to the RFA
to apply single cell epigenomic and transcriptomic technologies developed by our team to create cell-type-
specific epigenome and transcriptome maps in frontal cortex and hippocampus that are associated with AD-like
pathogenesis in two naturally occurring AD animal models: Octodon degus and Canis familiaris. These animals
show age-dependent neuropathology and cognitive impairment similar to those observed in human AD, thus
they are natural AD models. As both degus and mice are rodents, the studies of long-lived degus will be
particularly valuable for a within-mammalian order comparison of which AD gene regulatory pathways are
common to spontaneous AD-like features in degus versus different transgenic mouse models. While we
generate the resources in alignment with the RFA goals, the proposed research will allow us to develop a
comparative analysis to determine conserved epigenetic alterations in the unconventional animal models and
bridge our existing databases of mouse models and humans. Maladaptive changes in accessible chromatin
accessibility, chromatin organization and gene expression in disease relevant cell types will reveal species-
specific and cross-species conserved mechanisms of AD pathogenesis, as well as new targets for AD prevention
and treatment. This will provide new insights into the mechanisms of AD pathogenesis in humans. In addition
to genome data sharing at the designated NIH depository, resources will be shared and curated at our UCI
Center for Neural Circuit Mapping.

## Key facts

- **NIH application ID:** 10478202
- **Project number:** 5R24AG073198-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Carl Wayne Cotman
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,188,746
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478202

## Citation

> US National Institutes of Health, RePORTER application 10478202, Comparative Single-Cell Epigenomic Analysis of AD-like Pathogenesis in Unconventional Animal Models (5R24AG073198-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10478202. Licensed CC0.

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