Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice

Citation: Cell Death and Disease (2012) 3, e448; doi:10.1038/cddis.2012.189 & 2012 Macmillan Publishers Limited All rights reserved 2041-4889/12 www.nature.com/cddis Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice F Masciopinto 1,2,9 , N Di Pietro 3,9 , C Corona 1,2 , M Bomba 1,2 , C Pipino 3 , M Curcio 4 , A Di Castelnuovo 5 , D Ciavardelli 1,6 , E Silvestri 4 , LMT Canzoniero 4 , I Sekler 7 , A Pandolfi 3 and SL Sensi* ,1,2,8 In this study, we investigated the effects of long-term (9-month) treatment with pioglitazone (PIO; 20 mg/kg/d) in two animal models of Alzheimer’s disease (AD)-related neural dysfunction and pathology: the PS1-KI M146V (human presenilin-1 M146V knock- in mouse) and 3xTg-AD (triple transgenic mouse carrying AD-linked mutations) mice. We also investigated the effects on wild- type (WT) mice. Mice were monitored for body mass changes, fasting glycemia, glucose tolerance, and studied for changes in brain mitochondrial enzyme activity (complexes I and IV) as well as energy metabolism (lactate dehydrogenase (LDH)). Cognitive effects were investigated with the Morris water maze (MWM) test and the object recognition task (ORT). Behavioral analysis revealed that PIO treatment promoted positive cognitive effects in PS1-KI female mice. These effects were associated with normalization of peripheral gluco-regulatory abnormalities that were found in untreated PS1-KI females. PIO-treated PS1-KI females also showed no statistically significant alterations in brain mitochondrial enzyme activity but significantly increased reverse LDH activity.PIO treatment produced no effects on cognition, glucose metabolism, or mitochondrial functioning in 3xTg- AD mice. Finally, PIO treatment promoted enhanced short-term memory performance in WT male mice, a group that did not show deregulation of glucose metabolism but that showed decreased activity of complex I in hippocampal and cortical mitochondria. Overall, these results indicate metabolically driven cognitive-enhancing effects of PIO that are differentially gender-related among specific genotypes. Cell Death and Disease (2012) 3, e448; doi:10.1038/cddis.2012.189; published online 20 December 2012 Subject Category: Neuroscience Glucose dysmetabolism is a critical promoter of brain impairment. 1 Type 2 diabetes mellitus (T2DM), a disorder of peripheral glucose regulation, is also associated with cognitive decline. 2 Aging enhances the negative impact of T2DM on cognitive functions. 3 Interestingly, emerging evidence in the two past decades has shown that T2DM and Alzheimer’s Disease (AD) share common pathogenic mechanisms, 4 such as impaired glucose metabolism, increased oxidative stress, insulin resistance, and amyloidogenesis. Increased expression in the central nervous system of insulin receptors, not coupled with changes in Tyr-kinase activity, can lead to impairment of insulin signaling and is found in AD and T2DM patients. 5 In the brain, insulin signaling is not exclusively involved in metabolic processes but also has a role in modulating neurotrophic and neuroendocrine functions. 6 The hippocam- pus, a strategic area for cognition, contains substantial amounts of immunoreactive insulin and insulin receptors, 7 while hippocampal neurons have been shown to release insulin under depolarizing conditions. 8 Strengthening the importance of the insulin-cognition link, insulin receptor- defective mice have been reported to develop cognitive impairment. 9 Moreover, intranasal insulin administration has been shown to improve cognitive functions in diabetic and non-diabetic mice 10,11 as well as in humans, 12 an effect that is achieved without producing significant alterations in blood glucose levels. 13 Treatments aimed at improving insulin signaling have also been investigated for their neuroprotective potential in AD and in ischemic brain damage. 14 Thiazolidinediones (TZDs) act as Molecular Neurology Unit-Center of Excellence on Aging (Ce.S.I.), University ‘G. d’Annunzio’, Chieti-Pescara, Italy; 2 Department of Neuroscience and Imaging, University ‘G. d’Annunzio’, Chieti-Pescara, Italy; 3 Department of Experimental and Clinical Sciences, University ‘G. d’Annunzio’ and Ce.S.I., Chieti-Pescara, Italy; Department of Biological and Environmental Science, University of Sannio, Benevento, Italy; 5 Environmental and genetic epidemiology laboratory, Research Laboratories, FRC ‘Giovanni Paolo II’, Campobasso, Italy; 6 School of Engineering, Architecture, and Motor Science, ‘Kore’ University, Enna, Italy; 7 Department of Physiology, School of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel and 8 Departments of Neurology and Pharmacology, University of California-Irvine, Irvine, CA, USA *Corresponding author: SL Sensi, Molecular Neurology Unit, Ce.S.I., Via Colle dell’ Ara, Chieti 66013, Italy. Tel: þ 39 0871 541544; Fax: þ 39 0871 541542; E-mail: ssensi@uci.edu These authors contributed equally to this work. Keywords: pioglitazone; neurodegeneration; insulin signaling; glucose metabolism; mitochondrial complex activity; LDH Abbreviations: PIO, pioglitazone; AD, Alzheimer’s disease; WT, wild type; PS1-KI, human presenilin-1 M146V knock-in mouse; 3xTg-AD, triple transgenic mouse carrying AD-linked mutations; MWM, Morris water maze; ORT, object recognition test for object-place task; IPGTT, intraperitoneal glucose tolerance test; PPARg, peroxisome proliferator-activated receptor-g; APP, amyloid precursor protein; DI, Discrimination Index; TZD, thiazolidinedione; BN-PAGE, blue-native polyacrylamide gel electrophoresis; LDH, lactate dehydrogenase. Received 12.9.12; revised 8.11.12; accepted 15.11.12; Edited by A Verkhratsky