Facilitated By

San Antonio Medical Foundation

MEMBRANE LIPID PEROXIDATION IN PATHOGENESIS OF ALZHEIMER'S DISEASE

UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Ran, Qitao
Funded by
NIH-NATIONAL INSTITUTE ON AGING
Research Start Date
Status
Active

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 toattack by reactive oxygen species to result in lipid peroxidation. Lipid peroxidation is increased in AD brains andis believed to play a key role in driving neurodegeneration of AD. However, supplementation of lipid solubleantioxidants yields only mixed results in clinical trials. So the importance of lipid peroxidation in AD remainsunproven. Glutathione peroxidase 4 (Gpx4) is a glutathione peroxidase that can suppress lipid peroxidation bydirectly reducing phospholipid hydroperoxides in membranes. Therefore, Gpx4 suppresses lipid peroxidationthrough a mechanism distinct from that of lipid antioxidants. Gpx4's role in reducing phospholipid hydroperoxidesin 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 indicatingthat there is a Gpx4 dysfunction in AD brains that could lead to exacerbated pathogenesis and that enhancedGpx4 function retards cognitive impairment of AD mouse models. In this project, we will determine whetherincreased membrane lipid peroxidation induced by Gpx4 deficiency aggravates disease pathogenesis such asneurodegeneration, and determine the efficacy of Gpx4 overexpression in retarding cognitive impairment andneurodegeneration in AD mice. The overall hypothesis tested in this project is: Membrane lipid peroxidationaggravates A? neurotoxicity in vivo, and augmentation of Gpx4 function to suppress membrane lipid peroxidationwill retard AD pathogenesis. The hypothesis will be tested by three specific aims. Aim 1 is to determine the effectof membrane lipid peroxidation induced by Gpx4 deficiency on AD pathogenesis. Aim 2 is to determine whetheroverexpression of Gpx4 can suppress neurodegeneration and improve cognition in AD mice. Aim 3 is todetermine whether Gpx4 overexpression via transduction with viral vector can retard progression of disease inAD mice at different disease stages. Our study will establish the importance of membrane lipid peroxidation inneurodegeneration of AD and provide proof-of-concept evidence for the efficacy of Gpx4 as a target ofintervention to retard progression of AD.

Collaborative Project
Basic Research
Aging
Neuroscience