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The Journal of Neuroscience, December 13, 2006, 26(50):13102-13113; doi:10.1523/JNEUROSCI.3448-06.2006

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Neurobiology of Disease
Amyloid-ß-Induced Pathological Behaviors Are Suppressed by Ginkgo biloba Extract EGb 761 and Ginkgolides in Transgenic Caenorhabditis elegans

Yanjue Wu,¹ Zhixin Wu,² Peter Butko,³ Yves Christen,⁴ Mary P. Lambert,⁵ William L. Klein,⁵ Christopher D. Link,⁶ and Yuan Luo¹

¹Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, Departments of ²Biological Sciences and ³Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406, ⁴Ipsen, 75016 Paris, France, ⁵Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, and ⁶Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309

Correspondence should be addressed to Yuan Luo, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201. Email: yluo{at}rx.umaryland.edu

Amyloid-ß (Aß) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardized Ginkgo biloba extract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits Aß-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate Aß species with Aß-induced pathological behaviors in a model organism, Caenorhabditis elegans. We report that EGb 761 and one of its components, ginkgolide A, alleviates Aß-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenic C. elegans. We also show that EGb 761 inhibits Aß oligomerization and Aß deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress Aß-induced paralysis because the antioxidant L-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenic C. elegans. These findings suggest that (1) EGb 761 suppresses Aß-related pathological behaviors, (2) the protection against Aß toxicity by EGb 761 is mediated primarily by modulating Aß oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

Key words: Aß peptide; Alzheimer's disease; behavior; mutant; phenotype; serotonin

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Received Aug. 9, 2006; revised Oct. 12, 2006; accepted Nov. 9, 2006.

Correspondence should be addressed to Yuan Luo, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201. Email: yluo{at}rx.umaryland.edu

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