Abstract
Sporadic Alzheimer’s disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metabolism occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metabolism, pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the molecular mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 months and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clinical trials evaluating the efficacy of these drugs.
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This work was supported in part by the New York State Office for People with Developmental Disabilities as well as a grant from the Alzheimer’s Association (IIRG-10-170405). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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This paper is dedicated to late Professor Siegfried Hoyer, who made seminal contributions to our understanding of non-amyloid mechanisms of sporadic Alzheimer’s disease.
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Yu, Y., Li, X., Blanchard, J. et al. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice. J Neural Transm 122, 593–606 (2015). https://doi.org/10.1007/s00702-014-1294-z
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DOI: https://doi.org/10.1007/s00702-014-1294-z