# Regulation of CHCHD6 in Alzheimer's disease

> **NIH NIH RF1** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $2,136,033

## Abstract

PROJECT SUMMARY
 Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the population over
65. Processing amyloid-beta precursor protein (APP) into amyloid-beta peptide (Aβ) is an important and
fundamental aspect of AD pathogenesis. However, the signaling pathways that control this process are not
well defined. Mitochondrial dysfunction is a prominent early feature in susceptible neurons in the brain of
patients with AD and plays a critical role in AD pathogenesis. APP and its metabolic fragments are known to
localize to mitochondria where they negatively influence mitochondrial function. Conversely, neurons with
impaired mitochondrial function and bioenergetics also contribute to APP processing and synaptic loss.
Although evidence suggests that APP-mitochondrial interactions are important for the cognitive deficits and
amyloid genesis in AD, the field lacks a detailed understanding of the mechanisms that coordinate APP
processing and functional mitochondrial deficiency. The coiled-coil-helix-coiled-coil-helix domain-containing
protein 6 (CHCHD6) is an evolutionarily conserved nucleus-encoded mitochondrial protein. CHCHD6 is a core
component of the mitochondrial contact site and cristae organization system (MICOS), which controls
mitochondrial respiration and redox regulation, lipid homeostasis, and membrane ultrastructure and dynamics.
Recent proteomics studies have shown a decrease in CHCHD6 in brain samples of AD patients and AD mice.
However, the role of CHCHD6 in AD pathology is unknown. Our preliminary studies have revealed a previously
unidentified role of CHCHD6 in the regulation of APP-mediated neuropathology and cognitive
deficiency. The objective of this application is to determine the role of CHCHD6-mediated AD pathology at both
mechanistic and therapeutic levels. In Aim 1, we will determine the causes and consequences of CHCHD6
loss of function in AD models. In Aim 2, we will dissect the mechanism of CHCHD6 loss in AD pathology. In
Aim 3, we will determine whether compensation for the loss of CHCHD6 in AD mice alleviates neuropathology
and cognitive deficits. If successful, these studies will establish CHCHD6 as a key molecule linking APP
processing, lipid disturbance, and mitochondrial dysfunction and advance our understanding of AD pathology.
The findings generated by this project will also have a significant impact on AD research by identifying
CHCHD6 as a novel target for limiting mitochondrial dysfunction, amyloid pathology, and cognitive deficits in
AD.

## Key facts

- **NIH application ID:** 10461551
- **Project number:** 1RF1AG074346-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** XIN QI
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,136,033
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461551

## Citation

> US National Institutes of Health, RePORTER application 10461551, Regulation of CHCHD6 in Alzheimer's disease (1RF1AG074346-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10461551. Licensed CC0.

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