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P3‐340: Molecular basis of cognitive improvement of pioglitazone and rosiglitazone
Author(s) -
Li Xiaojing,
Yu Yang,
Blanchard Julie,
Liu Ying,
Iqbal Khalid,
Grundke-Iqbal Inge,
Gong Cheng-Xin
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1841
Subject(s) - pioglitazone , rosiglitazone , morris water navigation task , protein kinase b , pi3k/akt/mtor pathway , endocrinology , medicine , insulin , insulin receptor , insulin resistance , diabetes mellitus , type 2 diabetes , pharmacology , chemistry , phosphorylation , signal transduction , hippocampus , biochemistry
Background: Brain glucose uptake and metabolism are impaired in Alzheimer’s disease (AD), and this impairment appears to contribute to the pathogenesis of the disease. Insulin sensitizers, which are widely used for increasing insulin sensitivity and glucose utilization in diabetes, have shown some improvement in memory in AD mouse models and in AD clinical trials in AD patients. The present study was aimed to understand the possible molecular mechanisms by which two of these insulin sensitizers, pioglitazone and rosiglitazone, might cause the improvement. Methods: Ten-month-old female 3xTg-AD mice and the wild type controls were orally administered with pioglitazone (20 mg/kg body weight/day) and rosiglitazone (5 mg /kg body weight/day) for four months. Spatial memory was tested by using Morris water maze before and after the treatments. At the end of treatments and behavioral tests, the mice were sacrificed and the brain tissue was analyzed both by Western blots and immunohistochemistry for the insulin-PI3KAKT signaling pathway, phosphorylation and deposition of tau, Ab accumulation, and glial activation. Results: We observed that four-month treatments of 3xTg-AD mice with pioglitazone or rosiglitazone attenuated the deficits in spatial reference memory of the 3xTg-AD mice. These drug treatments also resulted in activation of protein kinase B (AKT) and inhibition of GSK-3b in the brain, suggesting activation of the insulin-PI3K-AKT signaling pathway. At the same time, hyperphosphorylation of tau at several sites, including Ser202, Thr217, Thr231, Ser404 and Ser422, Ab accumulation, and astrocyte over-activation were found to be attenuated in the drug-treated mice. Conclusions: Our results suggest that pioglitazone and rosiglitazone probably improve the memory deficits through several pathways, including elevation of insulin-PI3K-AKT signaling and attenuation of tau hyperphosphorylation, Ab accumulation, and inhibition of astrocyte over-activation. These findings suggest the potential usefulness of glitazones in the treatment for AD.