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

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 (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.

Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor γ Agonist Treatment Reduces Amyloid β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice

“…However, subsequent studies using PPAR agonists in several AD mouse models had variable success in observing changes in A␤ levels. Several studies using various treatment paradigms with PPAR␥ agonists observed decreases in soluble A␤ species (45,46), plaques (47,48) or both (27,36,49,50), and others reported decreased intracellular A␤ (51,52). However, there were also cases where PPAR␥ agonists exhibited no measurable effect on A␤ pathology (53)(54)(55).…”

“…LXR (9, 13, 18, 20 -24) and PPAR␥ (27,36,46,48,50,52,55,59,60) agonists have been reported to ameliorate memory deficits using a variety of tests in a range of mouse models. It should be noted, however, that Nicolakakis et al (53), Masciopinto et al (59), and Papadopoulos et al (54) reported no behavioral improvements after treating mice with pioglitazone.…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Administration of PPARc agonists improved cognitive function, suppressed inflammation, and reduced amyloid levels in many mouse models of AD (Camacho et al 2004;Combs et al 2000;Sastre et al 2003;Searcy et al 2012). In a rat AD model, injection of both ciglitazone and ibuprofen or oral pioglitazone administration potently suppressed Ab-caused microglial inflammatory reactions .…”

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Neuroprotective effects of the PPARg agonists rosiglitazone, pioglitazone, and 15-deoxy-prostaglandin J 2 were reported in studies of animal models of ischemic stroke (Bordet et al, 2006;Culman et al, 2007). It was shown that long-term treatment with pioglitazone improved cognitive deficits and AD-related pathology in a mouse model of AD (Sato et al, 2011;Gupta and Gupta, 2012;Searcy et al, 2012;Xiang et al, 2012). Neuroprotective effects of PPAR agonists have also been demonstrated in experimental models of PD (Chaturvedi and Beal, 2008;Ridder and Schwaninger, 2012).…”