# Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $385,000

## Abstract

ABSTRACT
 Alzheimer's disease (AD) is the most common neurodegenerative disease affecting millions of Americans.
Neurons have a large amount of polyunsaturated fatty acids in membrane phospholipids that are vulnerable to
attack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains and
is believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid soluble
antioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remains
unproven. Glutathione peroxidase 4 (Gpx4) is a glutathione peroxidase that can suppress lipid peroxidation by
directly reducing phospholipid hydroperoxides in membranes. Therefore, Gpx4 suppresses lipid peroxidation
through a mechanism distinct from that of lipid antioxidants. Gpx4's role in reducing phospholipid hydroperoxides
in cells such as neurons is critical and indispensable. Gpx4 also serves as the master regulator of ferroptosis.
We have demonstrated that Gpx4 plays a critical role in ensuring heath and survival of neurons in adult animals,
such as forebrain neurons that are severely afflicted in AD. In preliminary studies, we obtained data indicating
that there is a Gpx4 dysfunction in AD brains that could lead to exacerbated pathogenesis and that enhanced
Gpx4 function retards cognitive impairment of AD mouse models. In this project, we will determine whether
increased membrane lipid peroxidation induced by Gpx4 deficiency aggravates disease pathogenesis such as
neurodegeneration, and determine the efficacy of Gpx4 overexpression in retarding cognitive impairment and
neurodegeneration in AD mice. The overall hypothesis tested in this project is: Membrane lipid peroxidation
aggravates Aβ neurotoxicity in vivo, and augmentation of Gpx4 function to suppress membrane lipid peroxidation
will retard AD pathogenesis. The hypothesis will be tested by three specific aims. Aim 1 is to determine the effect
of membrane lipid peroxidation induced by Gpx4 deficiency on AD pathogenesis. Aim 2 is to determine whether
overexpression of Gpx4 can suppress neurodegeneration and improve cognition in AD mice. Aim 3 is to
determine whether Gpx4 overexpression via transduction with viral vector can retard progression of disease in
AD mice at different disease stages. Our study will establish the importance of membrane lipid peroxidation in
neurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Gpx4 as a target of
intervention to retard progression of AD.

## Key facts

- **NIH application ID:** 9983546
- **Project number:** 5R01AG064078-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** QITAO RAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983546

## Citation

> US National Institutes of Health, RePORTER application 9983546, Membrane lipid peroxidation in pathogenesis of Alzheimer’s disease (5R01AG064078-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983546. Licensed CC0.

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