Long-Term Pioglitazone Treatment Improves Learning and Attenuates Pathological Markers in a Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Searcy, James L.^{a; 1; 2} | Phelps, Jeremiah T.^{a; 1; 3} | Pancani, Tristano^{a; 4} | Kadish, Inga^b | Popovic, Jelena^a | Anderson, Katie L.^a | Beckett, Tina L.^c | Murphy, Michael P.^c | Chen, Kuey-Chu^a | Blalock, Eric M.^a | Landfield, Philip W.^a | Porter, Nada M.^a | Thibault, Olivier^{a; *}

Affiliations: [a] Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, Lexington, KY, USA | [b] Department of Cell Biology, University of Alabama, Birmingham, AL, USA | [c] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondence to: Olivier Thibault, Ph.D., University of Kentucky Medical Center, Department of Molecular and Biomedical Pharmacology, MS-313, UKMC, 800 Rose Street, Lexington, KY 40536-0084, USA. Tel.: +1 859 323 4863; Fax: +1 859 323 1981; E-mail: [email protected].

Note: [1] These authors contributed equally to the project.

Note: [2] Present address: Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, United Kingdom.

Note: [3] Present address: B327 Life Science, Michigan State University, East Landing, MI, USA.

Note: [4] Present address: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA.

Abstract: 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 (3xTg-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.

Keywords: 3xTg-AD, aging, hippocampus, long-term potentiation, microarray analysis, pioglitazone, PPAR, T2DM

DOI: 10.3233/JAD-2012-111661

Journal: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 943-961, 2012