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

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) (humanpresenilin-1 (M146V) knock-in mouse) and 3xTg-AD (triple transgenic mousecarrying AD-linked mutations) mice. We also investigated the effects on wild-type(WT) mice. Mice were monitored for body mass changes, fasting glycemia, glucosetolerance, 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 theobject recognition task (ORT). Behavioral analysis revealed that PIO treatmentpromoted positive cognitive effects in PS1-KI female mice. These effects wereassociated with normalization of peripheral gluco-regulatory abnormalities thatwere found in untreated PS1-KI females. PIO-treated PS1-KI females also showed nostatistically significant alterations in brain mitochondrial enzyme activity but significantly increased reverse LDH activity.PIO treatment produced no effects oncognition, glucose metabolism, or mitochondrial functioning in 3xTg-AD mice.Finally, PIO treatment promoted enhanced short-term memory performance in WT malemice, a group that did not show deregulation of glucose metabolism but thatshowed 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.