# Mitochondrial calcium uptake in Alzheimer’s disease

> **NIH NIH R00** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $242,702

## Abstract

Abstract: 
Alzheimer's disease (AD) is characterized by the loss of memory accompanied by neuronal cell death and 
metabolic dysfunction. Numerous studies have reported a dysregulation in neuronal intracellular calcium 
(1Ca2+) signaling as an early event in AD pathogenesis. It is thought that a prolonged elevation in neuronal 1Ca2+ 
promotes excessive mitochondrial calcium (mCa2+) uptake, yet to date no study has examined the contribution 
of mCa2+ uptake to disease progression. Since mCa2+ flux is an important regulator of cellular respiration and 
cell death, both of which are involved in AD pathogenesis, we hypothesize that mCa2+ overload is a key 
contributor to AD pathology and may contribute to metabolic deficits and neuronal demise. To define the role of 
mCa2+ exchange in AD we have generated 3xTg-AD mutant mice with neuronal-specific deletion of 
Mitochondrial Calcium Uniporter (MCU), which is required for mCa2+ uptake. In addition, we have generated a 
gain-of-function mutant mouse expressing the recently identified mitochondrial calcium uniporter beta subunit 
(MCUb). MCUb was recently reported as a negative regulator of mCa2+ uptake and we have observed 
substantial changes in its expression in AD. These models will allow causative experimentation to test if mCa2+ 
uptake drives AD progression. Mice will be examined for alterations in memory, amyloidosis, tau-pathology, 
oxidative stress, synaptic and metabolic function. Preliminary data suggest that mCa2+ uptake overload impairs 
the clearance of misfolded proteins and dysfunctional mitochondria. Therefore, we will mechanistically examine 
the link between mCa2+ exchange and autophagic and mitophagic pathways. Optimally, the proposed studies 
will discover new therapeutic targets for AD and associated mitochondrial dysfunction and provide a training 
and research platform to promote the Pis independent research career.

## Key facts

- **NIH application ID:** 10913460
- **Project number:** 5R00AG065445-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Pooja Jadiya
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $242,702
- **Award type:** 5
- **Project period:** 2020-08-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913460

## Citation

> US National Institutes of Health, RePORTER application 10913460, Mitochondrial calcium uptake in Alzheimer’s disease (5R00AG065445-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10913460. Licensed CC0.

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