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(American Journal of Pathology. 2007;170:1669-1678.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061178

Lithium Reduces Tau Phosphorylation but Not Aß or Working Memory Deficits in a Transgenic Model with Both Plaques and Tangles

From the Department of Neurobiology and Behavior, and Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California

Glycogen synthase kinase 3 (GSK-3) is a major kinase implicated in the pathogenesis of Alzheimer’s disease (AD), and reducing its activity may have therapeutic efficacy. Two variants exist, referred to as GSK-3 and GSK-3ß. In addition to the latter’s well-described role in the phosphorylation of tau, reports also suggest that GSK-3 may regulate amyloid precursor protein processing and Aß formation. The activities of both GSK-3 and GSK-3ß are reduced by lithium, a well-tolerated drug used in humans to combat bipolar disorder. Here, we investigate the therapeutic efficacy of chronic lithium administration in aged 3xTg-AD mice that harbor both plaques and tangles. We found that lithium reduced tau phosphorylation but did not significantly alter the Aß load. Despite the reduction in phosphotau, lithium treatment did not improve deficits in working memory. Although other studies have investigated the effects of lithium on tau biochemistry, this study represents the first to address comprehensively its therapeutic potential on other critical aspects of AD including its effect on Aß and learning and memory. It remains to be determined from human clinical trials whether lithium treatment alone will improve the clinical outcome in AD patients. These results, however, suggest that the most efficacious treatment will be combining lithium with other anti-Aß interventions.

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