Alzheimer's disease is the most common type of the debilitating types of dementia. It is characterized by a decrease in cognition, particularly among the elderly population. The condition is believed to be due to the accumulation of the beta amyloid protein (Ap) in the brain, particularly the hippocampus. This accumulation could be the result of protein overproduction or decreased clearance. Diabetes mellitus type 2 (DM2) has been reported as a risk factor for the development of the AD. Recent studies have proposed that the physiological conditions found in DM2 results in a 65% increased risk of developing AD. In 1997, Kuusisto's group showed that hyperinsulinemia, a condition associated with DM2, is a risk factor for AD in non-diabetic individuals. Insulin degrading enzyme (IDE) has been found to be involved in the clearance of Ap. It is also known that IDE has a high affinity for its other substrate, insulin. Interestingly AD patients present reduced IDE levels at the hippocampus. We propose that high levels of insulin, often found on DM2 patients, have repercussion on IDE resulting in increased accumulation of Ap in the brain. Recent studies report an impaired glucose metabolism in the AD mouse model Tg2576. The studies points out peripheral insulin resistance and hyperinsulinemia in the mice when compared with wild type mice. Based on these reports, we are interested in studying the effects on cognition resulting for the exposure of the mice with the peroxisome proliferator-activated receptor agonist (PPAR (rosiglitazone). Rosiglitazone is a drug shown to reduce hyperinsulinemia in diabetic mice. We are performing behavioral testing on these mice. Biochemical characterization will determine if the activity or level of the key enzymes in Ap and insulin catabolism are altered. Having a better understanding of the correlation between DM2 and AD will provide a stepping-stone in the development of potential treatments to forestall the physiological deterioration found in AD patients ? ? ? ?
| Denner, Larry A; Rodriguez-Rivera, Jennifer; Haidacher, Sigmund J et al. (2012) Cognitive enhancement with rosiglitazone links the hippocampal PPARýý and ERK MAPK signaling pathways. J Neurosci 32:16725-35a |
| Rodriguez-Rivera, Jennifer; Denner, Larry; Dineley, Kelly T (2011) Rosiglitazone reversal of Tg2576 cognitive deficits is independent of peripheral gluco-regulatory status. Behav Brain Res 216:255-61 |
