# Modulating Energy Metabolism as a Therapeutic Approach for Alzheimer's Disease

> **NIH NIH P01** · WINIFRED MASTERSON BURKE MED RES INST · 2020 · $505,100

## Abstract

Mitochondrial dysfunction and oxidative damage play an important role in the pathogenesis of Alzheimer's
disease (AD), and metabolic disturbances, such as reduced glucose utilization precede the β-amyloid and
tau pathology. We hypothesize that therapeutics targeting and correcting metabolic dysfunction will be
efficacious in treating AD. PGC-1α enhances both mitochondrial biogenesis and expression of antioxidant
enzymes, which produces neuroprotective effects both in vitro and in vivo. Sirtuins are NAD+ dependent
enzymes which play important roles in regulating metabolism. SIRT3 is of particular interest since it is
localized to mitochondria where it activates enzymes of energy metabolism, and protects against reactive
oxygen species (ROS) by increasing MnSOD and mitochondrial glutathione concentrations, and it inhibits
activation of the mitochondrial permeability transition by deacetylating cyclophilin D. We will examine
whether crossing transgenic mice with increased SIRT3 expression will exert neuroprotective effects in
transgenic mouse models with increased amyloid deposition (Tg19959 and APP-NL/G/F), or with
increased tau phosphorylation and NFTs (P301S). We will also determine whether treatment with
nicotinamide riboside (NR), which increases brain and mitochondrial NAD+ and activates SIRT1 and
SIRT3, will produce neuroprotective effects in Tg19959, APP-NL/G/F or P301S transgenic mice. The
peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is a group of ligand
modulated transcription factors that regulate gene expression of metabolic pathways, including PGC-1α.
We will determine whether the PPARα agonist palmitoylethanolamide (PEA), the PPARγ agonist
pioglitazone or the panPPAR agonist fenofibrate which modulate energy metabolism and inflammation,
are neuroprotective in transgenic mouse models of AD with either APP or tau mutations. Levels of
thiamine and the thiamine dependent enzymes α-ketoglutarate dehydrogenase and transketolase are
reduced in AD. Lastly, we will determine whether the lipid soluble thiamine analogue benfotiamine can
reduce oxidative stress and inflammation, and is neuroprotective in transgenic mouse models of AD with
either APP or tau mutations. We will utilize microPET and MRI to determine the time course of the
development of impaired glucose metabolism amyloid plaques (PIB) and tau (T807), which areas show
the most susceptibility, and whether these can be altered by therapeutic interventions including NR, PPAR
agonists and benfotiamine. These experiments are highly significant since they may lead to novel
treatments to slow or halt the cognitive impairment and neurodegenerative processes which occur in AD
and related dementias.

## Key facts

- **NIH application ID:** 9926809
- **Project number:** 5P01AG014930-19
- **Recipient organization:** WINIFRED MASTERSON BURKE MED RES INST
- **Principal Investigator:** M FLINT BEAL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $505,100
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926809

## Citation

> US National Institutes of Health, RePORTER application 9926809, Modulating Energy Metabolism as a Therapeutic Approach for Alzheimer's Disease (5P01AG014930-19). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9926809. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*