Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status

Abstract

Converging lines of evidence associate gluco-regulatory abnormalities and peroxisome-proliferator-activated receptor (PPAR) gamma function with increased risk for Alzheimer’s disease (AD). In this study, we used the Tg2576 AD mouse model to test the hypothesis that cognitive improvement following one-month of PPAR gamma agonism with rosiglitazone (RTZ) correlates with peripheral gluco-regulatory status. We assessed cognition and peripheral gluco-regulatory status of Tg2576 mice following one-month treatment with RTZ initiated prior to, coincident with, or after, the onset of peripheral gluco-regulatory abnormalities (4, 8, and 12-months of age, respectively). Whereas 5-months-old (MO) and 13 MO Tg2576 did not gain cognitive improvement after one-month treatment with RTZ, 9 MO Tg2576 mice exhibited reversal of associative learning and memory deficits. Peripheral gluco-regulatory abnormalities were improved in 9 and 13 MO Tg2576 with RTZ treatment; RTZ treatment had no effect on the normal glucose status of 5 MO Tg2576 mice. These findings suggest that RTZ-mediated cognitive improvement does not correlate with peripheral gluco-regulatory abnormalities per se, but reflects the age-dependent mechanistic differences that underlie cognitive decline in this mouse model.

β-Caryophyllene Ameliorates the Alzheimer-Like Phenotype in APP/PS1 Mice through CB2 Receptor Activation and the PPARγ Pathway

“…Indeed, PPARγ agonists have certain therapeutic effects on different experimental AD models [33,34,35,58,59]. To verify whether PPARγ was also involved in AD improvement after β-caryophyllene treatment, the PPARγ antagonist GW9662 (1 mg/kg, i.p.)…”

“…PPARγ is a member of the superfamily of nuclear receptors and has important anti-inflammatory activity [28,29], because it inhibits the activation of nuclear factor-κB and the expression of the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) [30,31,32]. There is now an extensive body of evidence that has demonstrated the efficacy of PPARγ agonists in ameliorating disease-related pathology and improving learning and memory in animal models of AD [33,34,35]. Recent clinical trials of the PPARγ agonist rosiglitazone have also shown significant improvement in memory and cognition of AD patients [36,37].…”

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

“…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.…”

A Review: Treatment of Alzheimer’s Disease Discovered in Repurposed Agents

“…In vitro studies have shown synergistic neuroprotective effects when rosiglitazone is administered with insulin, whereas partial neuroprotection occurs with rosiglitazone treatment alone [57]. Several animal model studies of AD have demonstrated reduced cognitive impairment, Aβ oligomers, and inflammation with rosiglitazone treatment [58,59,60,61,62]. Rosiglitazone’s anti-AD effects are independent of its effect on glucose regulation [59].…”