# The tricarboxylic acid (TCA) cycle in neurodegeneration

> **NIH NIH P01** · WINIFRED MASTERSON BURKE MED RES INST · 2020 · $590,806

## Abstract

Reduced glucose metabolism always accompanies Alzheimer's disease (AD) and the decline is highly
correlated with the decline in cognition. Promotion of AD pathology by manipulation of glucose/oxygen
utilization in pre-clinical models supports the possibility that these deficits are not mere consequences of the
disease, but promote the disease and are potential therapeutic targets. An understanding of the underlying
basis for the decline in glucose utilization and its consequences are required to therapeutically target glucose
utilization. The decline in mental function before AD patients die is highly correlated to changes in the activities
of enzymes related to the mitochondrial tricarboxylic acid (TCA) cycle including the entry level enzyme- the
pyruvate dehydrogenase complex (PDHC) and the rate controlling step-α-ketoglutrate dehydrogenase
(KGDHC. The proposed studies will test the overall hypothesis that the changes in the TCA cycle underlie the
abnormal metabolism and pathology in AD and that reversing them or the downstream consequences will
benefit AD patients. We propose that determining the post-translational modifications that diminish the activity
of KGDHC in brains from AD patients will reveal the cause of the modification and suggest effective ways to
reverse the deficit. The possibility that KGDHC and PDHC may directly modify other TCA cycle enzymes will
be tested. The experiments will test whether diminished KGDHC alters the response to drugs that promote
mitogenesis and determine the link between the KGDHC and signals for mitochondrial repair in order to
manipulate them to enhance mitochondrial repair. Surprisingly little is known about the response of the genes
and proteins of the entire TCA cycle to metabolic perturbations and some “mitogenic” therapies may diminish
activities. Thus, the proposal is to test the response of these enzymes at the level of the gene, activity and
protein (including post-translational modifications by acetyl or succinyl groups) to select metabolic
perturbations to determine better therapeutic targets. The experiments will test the hypothesis that changes in
the mitochondrial TCA cycle and the consequent downstream signaling changes are central to the disease
process and provide a therapeutic target that is not responsive to mitogenic therapies. Successful completion
of these studies will identify additional mechanisms to reverse the deficits and ameliorate the disease process.

## Key facts

- **NIH application ID:** 9926808
- **Project number:** 5P01AG014930-19
- **Recipient organization:** WINIFRED MASTERSON BURKE MED RES INST
- **Principal Investigator:** GARY E GIBSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $590,806
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926808

## Citation

> US National Institutes of Health, RePORTER application 9926808, The tricarboxylic acid (TCA) cycle in neurodegeneration (5P01AG014930-19). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9926808. Licensed CC0.

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