# Mitochondrial calcium uptake in Alzheimer's disease

> **NIH NIH K99** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $104,095

## 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
(iCa2+) signaling as an early event in AD pathogenesis. It is thought that a prolonged elevation in neuronal
iCa2+ 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:** 10239248
- **Project number:** 5K99AG065445-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Pooja Jadiya
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $104,095
- **Award type:** 5
- **Project period:** 2020-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239248

## Citation

> US National Institutes of Health, RePORTER application 10239248, Mitochondrial calcium uptake in Alzheimer's disease (5K99AG065445-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10239248. Licensed CC0.

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