# TOMM40-mediated mitochondrial dysfunction and Alzheimers disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $556,449

## Abstract

Summary
Mitochondrial dysfunction and synaptic damage are early pathological features of the
Alzheimer's disease (AD) affected brain. Aβ has deleterious effects on mitochondrial and
synaptic dysfunction. The underlying mechanisms and strategies to rescue such injury remain
unclear. Recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis.
Accumulation of mitochondrial Aβ may be an initiating pathological event leading to
mitochondrial and neuronal perturbation. TOMM40 (Translocase of the Outer Mitochondrial
Membrane-40kD) is the key subunit of the TOM complex, the main entry channel for the vast
majority of imported proteins must pass to enter the mitochondrial interior. A polymorphism
inTOMM40 is associated with an increased risk of late-onset AD and decreased cognitive
performance48. This polymorphism is the only nuclear-encoded gene identified in genetic
studies to date that presumably contributes to LOAD-related mitochondrial dysfunction. Aβ and
APP can be imported into the mitochondria through the TOMM40 channel in an in vitro cell
culture, however, the TOMM40-mediated Aβ import mechanism remains unclear and the impact
of TOMM40 on amyloid pathology, mitochondrial and synaptic degeneration, and
neuroinflammation in Aβ milieu have not yet been elucidated. In our pilot studies, we observed
that TOMM40 knockdown mice displayed significantly reduced mitochondrial Aβ levels, along
with improvement in mitochondrial and synaptic function in Tg mAPP mice overexpressing Aβ.
Furthermore, reduced TOMM40 levels in Tg mAPP mice attenuate the innate immune and
proinflammatory response. These data suggest that TOMM40 may potentially be of importance
in mitochondrial amyloid pathology of AD. We hypothesize that impaired function of TOMM40
contributes to chronic mitochondrial Aβ accumulation relevant to developing amyloid pathology
of AD, leading to mitochondrial and synaptic degeneration. The goal of this proposal is to gain
new insight into the role of TOMM40 in AD pathogenesis, focusing on mitochondrial Aβ
accumulation/clearance, amyloid pathology, synaptic mitochondrial properties, oxidative stress,
inflammation, and synaptic function, utilizing a novel genetically manipulated transgenic
TOMM40/AD mouse models and neuronal culture with altered TOMM40 levels (gaining/losing)
in an Aβ-rich environment (genetic deficiency of global and neuronal TOMM40 and increased
neuronal TOMM40 in AD-type transgenic mice overexpressing Aβ). The outcomes of the project
could present that TOMM40 might be a potential new therapeutic target for limiting
mitochondrial amyloid pathology thereby halting AD progression.

## Key facts

- **NIH application ID:** 9990641
- **Project number:** 5R01AG053041-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Shirley ShiDu Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,449
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990641

## Citation

> US National Institutes of Health, RePORTER application 9990641, TOMM40-mediated mitochondrial dysfunction and Alzheimers disease (5R01AG053041-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990641. Licensed CC0.

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