# Mitochondrial ATP Synthase Dysfunction and Synaptic Stress in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2020 · $374,192

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Du, Heng
Project summary:
Increasing evidence has suggested that mitochondrial dysfunction plays a central role in the pathogenesis of
Alzheimer's disease (AD) . Compromised synaptic mitochondrial capabilities in ATP production and calcium
retention have been proposed to be underlying the early synaptic injury in Aβ-rich milieus. However, the detailed
molecular mechanisms of such Aβ-potentiated synaptic mitochondrial deficits still remain elusive. The specific
hypothesis behind this proposed study is that mitochondrial F1Fo ATP synthase dysfunction via oligomycin
sensitivity conferring protein (OSCP) aberrations is a potential cause of synaptic mitochondrial defects, leading
to synaptic failure in AD-relevant conditions. This hypothesis is firmly built on the following observations: First,
Mitochondrial F1Fo ATP synthase plays a vital role in ATP generation ; and uncoupled F1Fo ATP synthase
constitutes the molecular basis of mitochondrial permeability transition pore (mPTP) , the opening of which
lowers mitochondrial ability to buffer calcium .Its dysfunction has been implicated in aging brain and AD; but the
mechanisms are not well understood; Second, in preliminary studies we have found that mitochondrial F1Fo
ATP synthase dysfunction is a prominent synaptic mitochondrial defect in an AD animal model overexpressing
APP/Aβ (5xFAD mice); Third, our further studies on this enzyme in AD brains and synaptic mitochondria from
5xFAD mice have shown the selective loss of its OSCP subunit and the interaction of OSCP with Aβ.
Furthermore, such OSCP alterations disrupt the integrity and function of mitochondrial F1Fo ATP synthase.
Lastly, the restoration of OSCP expression mitigates Aβ-induced neuronal mitochondrial and synaptic
dysfunction. In the proposed studies, we will adopt multiple tools including our newly generated neuron-specific
OSCP overexpressing 5xFAD mice, a decoy peptide to inhibit OSCP/Aβ interaction as well as genetic OSCP
down-regulation and apply multidisciplinary approaches of biochemistry, cell and molecular biology,
electrophysiology and live cell imaging. We aim to firmly establish the link between OSCP aberrations and
synaptic mitochondrial F1Fo ATP synthase deregulation in AD-relevant condition and determine its impact on
the development of synaptic mitochondrial dysfunction (Specific aim1) and synaptic injury/cognitive impairments
(specific aim2) in 5xFAD mice. Furthermore, we will address the mechanisms of Aβ-mediated mitochondrial
OSCP deficiency (specific aim3). The positive findings will provide a novel mechanism of mitochondrial and
synaptic defects in AD and shed light on the development of novel therapeutic strategies for the treatment of AD
by the protection of OSCP. In addition, the results can be extended to further our understanding of mitochondrial
dysfunction and synaptic failure in other neurodegenerative diseases which have Amyloid beta (Aβ) deposition...

## Key facts

- **NIH application ID:** 10266216
- **Project number:** 7R01AG053588-06
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Heng Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,192
- **Award type:** 7
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10266216

## Citation

> US National Institutes of Health, RePORTER application 10266216, Mitochondrial ATP Synthase Dysfunction and Synaptic Stress in Alzheimer's Disease (7R01AG053588-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10266216. Licensed CC0.

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