Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer's Disease
| Autor: | Tristano Pancani, Inga Kadish, Kuey-Chu Chen, Nada M. Porter, Jelena Popovic, Eric M. Blalock, James L. Searcy, Michael Paul Murphy, Katie L. Anderson, Philip W. Landfield, Olivier Thibault, Tina L. Beckett, Jeremiah T. Phelps |
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| Rok vydání: | 2012 |
| Předmět: |
Genetically modified mouse
medicine.medical_specialty Time Factors Peroxisome proliferator-activated receptor Mice Transgenic Type 2 diabetes Biology Drug Administration Schedule Article Mice Alzheimer Disease Internal medicine medicine Animals Learning Cognitive decline Brain Chemistry chemistry.chemical_classification Pioglitazone General Neuroscience Long-term potentiation General Medicine medicine.disease Disease Models Animal Psychiatry and Mental health Clinical Psychology Endocrinology chemistry Female Thiazolidinediones Animal studies Geriatrics and Gerontology Alzheimer's disease Biomarkers medicine.drug |
| Zdroj: | Journal of Alzheimer's Disease. 30:943-961 |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer’s disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3×Tg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the TZD pioglitazone (PIO-Actos®) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short- and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. |
| Databáze: | OpenAIRE |
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