The thiazolidinediones, such as rosiglitazone, increase peripheral insulin sensitivity and their use is proposed for the treatment of Alzheimer’s disease (AD). However, the mechanisms underlying the potential beneficial effects of rosiglitazone in AD remain unclear. In this report the authors demonstrate that rosiglitazone attenuates spatial learning and memory deficits in the Tg2576 transgenic mouse model of AD. The authors further show that rosiglitazone administration ameliorated the age –dependent peripheral insulin resistance and increased serum corticosterone levels exhibited by fasting Tg2576 mice. These data suggest that the beneficial effects of rosiglitazone on cognitive function of Tg2576 mice may be, at least partially, due to improved regulation of glucocorticoid levels. When untreated Tg2576 mice were administered metyrapone, a drug that blocks glucocorticoid production, their spatial learning and memory abilities and serum corticosterone levels were similar to those of rosiglitazone-treated mice- thus supporting the connection between glucocorticoid levels-rosiglitazone treatment and cognitive function. In addition, the authors report that that rosiglitazone attenuated reductions in insulin-degrading enzyme (IDE) mRNA and activity, and reduced beta amyloid peptide 42 (Aβ)42 levels without affecting beta amyloid deposition, in the brains of Tg2576 mice. These results demonstrate that rosiglitazone attenuates learning and memory deficits in Tg2576 mice and suggest that the effects of the drug on learning and memory, brain IDE levels, and brain Aβ42 levels in the mice may be due to its glucocorticoid-lowering actions. While the mechanisms remain to be elucidated, an implication of these results is that rosiglitazone may be effective at attenuating changes in the brain leading to cognitive dysfunction in AD. Supporting this therapeutic hypothesis are clinical studies showing that rosiglitazone prevents cognitive decline in patients with early AD (see below –Watson et,al., 2005).
Dose was determined in tolerability studies reported in the following: Q.N. Diep, M.E. Mabrouk, J.S. Cohn, D. Endemann, F. Amiri, A. Virdis, M.F. Neves, E.L. Schiffrin
Structure, endothelial function, cell growth, and inflammation in blood vessels of angiotensin II-infused rats: role of peroxisome proliferator-activated receptor-γ Circulation, 105 (2002), pp. 2296–2302.