# Relationships between APP and Mitochondria

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $739,197

## Abstract

Project Summary/Abstract
 We will determine the effects of APP and APP proteolytic products on mitophagy and
bioenergetic function. We hypothesize that amyloid precursor protein (APP) facilitates mitophagy through
direct interactions with PINK1 and p62. We further hypothesize that loss of APP expression or reduced
mitochondrial localization affects mitochondrial function through inhibition of mitophagy.
 Metabolic deficiencies are prominent in Alzheimer’s disease (AD). A clear relationship between amyloid
precursor protein (APP) and mitochondria is described in the literature but the function of APP at
mitochondria is not well understood.
 APP and Aβ localize to mitochondria and can alter mitochondrial function. Our data show that
mitochondrial membrane potential directly correlates with Aβ production and APP mitochondrial localization.
Under conditions of increased mitophagy APP mitochondrial localization is increased. Our data indicate loss of
APP at mitochondria or loss of APP expression, reduces mitochondrial electron transport chain (ETC) function
and mitophagy. Overall, our data support a role of APP in modulating mitophagy and bioenergetic flux. A
current gap in our knowledge is if these observations are attributed to full-length APP or APP
processing products. We will address this knowledge gap here.
 A relationship between mitochondria, bioenergetics, mitophagy, and APP is evident. Our data support a
relationship between APP localization at mitochondria, bioenergetic function, and mitophagy. We hypothesize
that loss of APP at mitochondria alters bioenergetic flux (Aim 1) and mitochondrial localized APP
facilitates mitophagy (Aim 2). The overall goal of this study is to understand the role of APP and its
derivatives in mitophagy and bioenergetic flux.
 We will use in vivo and in vitro models across two aims. In vitro models include engineered induced
pluripotent stem cells (iPSC) cells with either wild-type (WT) APP, APP knockout, or mitochondrial localization
incompetent APP (3M APP) expression. Engineered iPSCs will be differentiated to neurons and astrocytes. In
vivo models will include non-transgenic, transgenic WT APP mice and APP knockout mice. Use of both in vivo
and in vitro models allows for elucidation of cell type specific effects (in vitro models) and sex differences (in
vivo).
 We will measure endpoints in the models proposed under native conditions and under conditions where
APP processing is inhibited or increased. We will determine the role of full-length APP versus APP processing
products in mitophagy and bioenergetic flux pathways.

## Key facts

- **NIH application ID:** 10833691
- **Project number:** 5R01AG078186-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Heather M. Wilkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $739,197
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833691

## Citation

> US National Institutes of Health, RePORTER application 10833691, Relationships between APP and Mitochondria (5R01AG078186-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10833691. Licensed CC0.

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