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The Journal of Neuroscience, February 21, 2007, 27(8):1981-1991; doi:10.1523/JNEUROSCI.4321-06.2007
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Neurobiology of Disease
Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3ß Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation
Edward Rockenstein,1 Magdalena Torrance,1 Anthony Adame,1 Michael Mante,1 Pazit Bar-on,1 John B. Rose,1 Leslie Crews,2 andEliezer Masliah1,2 Departments of 1 Neurosciences and 2Pathology, University of California, San Diego, La Jolla, California 92093
Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu
The glycogen synthase kinase-3ß (GSK3ß) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3ß activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3ß is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3ß pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3ß tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN–GSK3ß tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3ß was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-ß production. In conclusion, the present study showed that modulation of the GSK3ß signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3ß might be a suitable target for the treatment of AD.
Key words: lithium; Alzheimer's disease; APP; amyloid; GSK3ß; phosphorylation
Received Jan. 26, 2006; accepted Oct. 27, 2006.
Correspondence should be addressed to Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624. Email: emasliah{at}ucsd.edu
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