# Interplay between amyloid precursor protein metabolism and ER-mitochondria contact

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $196,750

## Abstract

Alzheimer's disease (AD) remains a looming public health crisis, despite intensive research and
pharmaceutical development efforts. No effective treatment option is currently available that can halt the
disease process. The recent failures of high-profile clinical trials targeting the amyloid plaques and
neurofibrillary tangles, the pathological hallmarks of the AD identified by Dr. Alois Alzheimer more than a
century ago and the focus of extensive research and pharmaceutical development efforts, suggest that new
directions in delineating the pathogenic mechanisms of AD are warranted before effective treatment of the
disease can be achieved.
 Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from
energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions
position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are
intimately linked. In addition to the central role of mitochondria in bioenergetics, they are also critically
important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+
transients arising from neuronal activation, protecting against the detrimental effects of bursts of Ca2+ influx.
Under basal conditions, Ca2+ entry into mitochondria is needed for normal neuronal physiology. The ER-
mitochondria contact site (ERMCS) are recognized as key cellular structures regulating mito-Ca2+ homeostasis.
Moreover, there is an emerging recognition of ERMCS impairment in neurodegenerative diseases including
AD. How ERMCS and mito-Ca2+ homeostasis are altered, and their contribution to disease phenotypes in in
vivo settings, however, are not well understood. The goal of this proposal is to test the central hypothesis that
an interplay between APP metabolism and ERMCS directs ER-mitochondrial Ca2+ signaling, and that defects in
this process contributes to the etiology of AD. To test this hypothesis, we propose to achieve the following
Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in a Drosophila AD
model and AD patient derived cells; Aim 2. Test the roles of ERMCS proteins that direct mito-Ca2+ homeostasis
in mediating APP function in disease pathogenesis. By providing evidence for the involvement of ERMCS and
mito-Ca2+ in APP function at the organellar, synaptic, and organismal levels, these studies will lay the
foundation for future studies addressing the regulation and function of ERMCS in normal brain physiology,
which will significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling
in AD and ultimately offer novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10470218
- **Project number:** 5R21AG074414-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Bingwei Lu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,750
- **Award type:** 5
- **Project period:** 2021-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470218

## Citation

> US National Institutes of Health, RePORTER application 10470218, Interplay between amyloid precursor protein metabolism and ER-mitochondria contact (5R21AG074414-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10470218. Licensed CC0.

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