# Targeting CHCHD10 to mitigate Alzheimer's disease pathogenesis

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $383,010

## Abstract

PROJECT SUMMARY
Our preliminary studies show that the FTD/ALS-associated mitochondrial protein, CHCHD10, declines in brains
of APP/PS1 mice and human AD patients, which negatively correlates with Aβ levels. Restoration of CHCHD10
in APP/PS1 mice reduces Aβ deposition in vivo. In transfected cells, wild type CHCHD10 promotes mitochondrial
respiration as well as mitophagy and autophagy via PINK1/Parkin and p62/LC3 pathways. In aim 1, we take
advantage of the APP/PS1 AD model, our newly generated CHCHD10 transgenic mice, and the mitophagy
reporter mice (mito-QC) to test the hypothesis that CHCHD10 restoration mitigates Aβ pathology and
neuroinflammation while enhancing mitochondrial function, synaptic integrity, synaptic plasticity, and mitophagy
flux in APP/PS1 mice. Natural antisense transcripts (NATs) located on the opposite strand of sense genes can
suppress expression of sense genes. Therefore, suppression of NATs by short sense oligonucleotides targeting
NATs (antagoNATs) can upregulate sense gene expression. As preliminary studies show that Aβ42 oligomers
reduce CHCHD10 mRNA and protein, we will test the hypothesis that CHCHD10 reduction in APP/PS1 mouse
brains and Aβ42 oligomer treated primary neurons is, at least in part, due to increases in specific NATs
suppressing endogenous CHCHD10 expression. Indeed, we have identified several mouse NATs expressed in
the antisense direction of CHCHD10, and expression of short sense oligonucleotides targeting CHCHD10 NATs
(antagoNATs) significantly increase endogenous CHCHD10 expression. Hence, we will extend studies to
human neurons directly converted from primary fibroblasts. Specifically, we will test the hypothesis that
corresponding CHCHD10 NATs are expressed in human neurons, that such NATs and CHCHD10 are inversely
regulated by Aβ oligomers, and that antagoNATs directed against CHCHD10 NATs not only increase CHCHD10
expression (mRNA & protein) but also protect against Aβ42 oligomer-induced defects in mitochondrial function
in human neurons.
Successful conclusion of this study will: 1. Validate the role of CHCHD10 in promoting mitochondrial health and
autophagy/mitophagy to reduce Aβ deposition and synaptic integrity/function in brain. 2. Identify a potential
mechanistic basis for CHCHD10 decline in AD; 3. Establish an important platform for developing an antagoNAT
strategy to therapeutically increase CHCHD10 levels in mice and humans, an approach that could be applied to
targets beyond CHCHD10 and diseases beyond AD.

## Key facts

- **NIH application ID:** 10517528
- **Project number:** 7R21AG070299-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tian Liu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,010
- **Award type:** 7
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517528

## Citation

> US National Institutes of Health, RePORTER application 10517528, Targeting CHCHD10 to mitigate Alzheimer's disease pathogenesis (7R21AG070299-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10517528. Licensed CC0.

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