# Defining Strategies to Target Energy Failure in Metabolically Vulnerable Human Cells

> **NIH NIH R01** · J. DAVID GLADSTONE INSTITUTES · 2022 · $460,375

## Abstract

PROJECT SUMMARY
Mitochondrial dysfunction and protein misfolding are central pathological processes in aging and aging-
associated neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD),
but the relationship between these processes is poorly understood, as are the mechanisms by which they lead
eventually to cell death. Although mitochondrial dysfunction occurs in AD, little is understood about the
consequences of this mitochondrial failure or how it contributes to neurodegeneration, especially its impact on
protein misfolding. To gain insight into how mitochondria impact protein misfolding, we used innovative high
throughput CRISPR-based screens to identify critical roles for the mitochondrial respiratory chain as well as
genes that regulate ATP and reactive oxygen species (ROS) levels in the regulation of tau misfolding. In this
proposal, we will test our central hypothesis that in AD, age-associated mitochondrial dysfunction impairs tau
homeostasis, and that increasing ATP and decreasing ROS can decrease tau misfolding and cell death. The
overall objectives of our proposed study are to determine how mitochondrial respiratory chain dysfunction
regulates tau aggregation, and define the most robust mechanisms to prevent tau-induced neurodegeneration.
We will accomplish these objectives in two specific aims. (1) We will use pharmacologic inhibitors and gene
knockdown with assays of energy levels and oxidative stress to gain insight into the consequences of
mitochondrial perturbation. We will also use transcriptomics to identify broad mechanisms by which metabolic
dysfunction promotes tau misfolding in human neurons. (2) We will determine how increasing energy or
decreasing ROS can decrease protein misfolding and enhance neuronal survival in models of AD. Overall, these
studies will yield new information about the causal relationships between metabolic failure and protein
aggregation in AD, and begin to reveal new therapeutic strategies to target metabolic dysfunction in AD.

## Key facts

- **NIH application ID:** 10499966
- **Project number:** 3R01AG065428-03S1
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** KEN NAKAMURA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $460,375
- **Award type:** 3
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499966

## Citation

> US National Institutes of Health, RePORTER application 10499966, Defining Strategies to Target Energy Failure in Metabolically Vulnerable Human Cells (3R01AG065428-03S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10499966. Licensed CC0.

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