Identifying a novel antioxidant target for Alzheimer's disease therapy

Cynthia Massaad, PhD
Baylor College of Medicine (Houston, TX)

Mentors

Robia Pautler, Ph.D.
Baylor College of Medicine
Year Awarded:
2008
Grant Duration:
April 1, 2008 to October 31, 2010
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2008600
Award Type:
Postdoctoral Fellowship
Award Region:
US Southern

The Role of Mitochondrial Superoxide in Alzheimer's Pathology

Summary

This project examines the role of antioxidants in mouse models of Alzheimer's disease. The study will examine the pathophysiological basis of the disease using Magnetic Resonance Imaging (MRI). The outcomes of this project will predict ways of using antioxidant therapy to overcome Alzheimer's disease.

Details

Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposition of amyloid plaques leading to dementia and memory loss. Oxidative stress is a condition in which reactive oxygen molecules damage cells at a rate greater than the body's ability to repair that damage. It is also associated with the pathology of Alzheimer's disease. It is believed that amyloid beta accumulation and oxidative stress are linked; it is not known however which comes first. Our project aims at understanding the role of oxidative stress in AD via using 2 animal models: an AD model and a model that overexpresses an antioxidant enzyme. We are in a unique position not only to study the biochemical and behavioral effects, but also the physiological effects of antioxidants on AD symptoms. We specifically propose to (1) measure the increase of various amyloid beta types in AD mice at several age points and test whether this increase is alleviated by an increased antioxidant protection. (2) measure the integrity of axonal transport (indicative of nerve cell integrity) in AD model mice by in imaging with MRI techniques, and test the effect of antioxidant protection using the same technique. (3) Measure blood flow in the brain of AD model mice and test whether increased antioxidant protection will be beneficial. This aim will be achieved using specialized MRI imaging. The results of this study are extremely important to identify novel targets for the design and use of pharmacological antioxidant agents for the treatment of AD.

Publications

Massaad, C.A., Washington, T.M., Pautler, R.G. and Klann, E. (2009) Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA. 106(32), 13576-13581  

(This study reports the involvement of mitochondrial superoxide in AD-related elevation of ABeta levels and learning and memory deficits. Understanding the mechanism of action of such an involvement offers an attractive target candidate for the treatment of AD. This study was the subject of a media report entitled 'Enzyme stymies Alzheimer's effect in mice'. The media report can be found at: http://www.bcm.edu/news/item.cfm?newsID=1503)

Massaad, C.A., Pautler, R.G. and Klann, E. (2009) Mitochondrial superoxide: a key player in Alzheimer's disease pathology. Aging. 1(9), 758-761  

Paper available online at: www.impactaging.com

(This invited commentary discusses the report mentioned in 1 in the context of new literature findings and addresses potential future directions that the study may evolve into.)

Massaad, C.A., Amin, S.K., Hu, L., Klann, E. and Pautler R.G. (Sept. 2009) Mitochondrial free radicals play a critical role in Alzheimer's disease pathology. The Texas brain and spine institute annual neuroscience symposium on Alzheimer's disease, College Station, Texas, USA

(This study reports the involvement of mitochondrial superoxide in AD-related blood flow and axonal transport deficits. Understanding the mechanism of action of such an involvement offers an attractive target candidate for the treatment of AD.)

Massaad, C.A., Amin, S.K., Hu, L., Mei, Y., Klann, E. and Pautler R.G. (Jan. 2010) Mitochondrial free radicals play a critical role in Alzheimer's disease-related blood flow and axonal transport deficits. The Keystone Symposia - Alzheimer's disease, Copper Mountain, Colorado, USA [conference abstract]

(This study reports the involvement of mitochondrial superoxide in AD-related blood flow and axonal transport deficits. This involvement occurs via modulation of eNOS and tau actions, respectively. Further understanding of the mechanism of action of such an involvement offers an attractive target candidate for the treatment of AD.)

Massaad, C.A., Amin, S.K., Hu, L., Mei, Y., Klann, E. and Pautler, R.G. (2010) Overexpression of SOD‐2 ameliorates cerebral blood flow and reverses axonal transport deficits in a mouse model of Alzheimer's disease. PLoS ONE. 5 (5), e10561 PubMed Icon Google Scholar Icon

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.