Effects of ageing and experimental diabetes on insulin-degrading enzyme expression in male rat tissues.

Due to an increasing life expectancy in developing countries, cases of type 2 diabetes and Alzheimer's disease (AD) in the elderly are growing exponentially. Despite a causative link between diabetes and AD, general molecular mechanisms underlying pathogenesis of these disorders are still far from being understood. One of the factors leading to cell death and cognitive impairment characteristic of AD is accumulation in the brain of toxic aggregates of amyloid-ß peptide (Aß). In the normally functioning brain Aß catabolism is regulated by a cohort of proteolytic enzymes including insulin-degrading enzyme (IDE) and their deficit with ageing can result in Aß accumulation and increased risk of AD. The aim of this study was a comparative analysis of IDE expression in the brain structures involved in AD, as well as in peripheral organs (the liver and kidney) of rats, during natural ageing and after experimentally-induced diabetes. It was found that ageing is accompanied by a significant decrease of IDE mRNA and protein content in the liver (by 32 and 81%) and brain structures (in the cortex by 58 and 47% and in the striatum by 53 and 68%, respectively). In diabetic animals, IDE protein level was increased in the liver (by 36%) and in the striatum (by 42%) while in the brain cortex and hippocampus it was 20-30% lower than in control animals. No significant IDE protein changes were observed in the kidney of diabetic rats. These data testify that ageing and diabetes are accompanied by a deficit of IDE in the brain structures where accumulation of Aß was reported in AD patients, which might be one of the factors predisposing to development of the sporadic form of AD in the elderly, and especially in diabetics.

Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes.

Alzheimer's disease (AD) is linked to certain common brain pathologies (e.g., ischemia, stroke, and trauma) believed to facilitate its development and progression. One of the logical approaches to this problem is to study the effects of ischemia and hypoxia on the metabolism of amyloid precursor protein, which plays one of the key roles in the pathogenesis of AD. This involves an analysis of (1) proteases, which participate in proteolysis of amyloid precursor protein either by the nonamyloidogenic route (alpha-secretase) or the amyloidogenic pathway and lead to formation of toxic beta-amyloid peptides (beta- and gamma-secretases) and (2) several metallopeptidases that might play a role in degradation of beta-amyloid peptide (Abeta). The study of the effects of prenatal hypoxia and acute hypoxia in adult animals allowed us to conclude that oxygen deprivation results not only in an increase of amyloid precursor protein expression in the brain but also in a decrease in the activity of alpha-secretase. In some brain structures involved in AD pathology (the cortex and striatum), we also observed a decrease in the expression of two of the Abeta degrading enzymes, neprilysin and endothelin-converting enzyme, after hypoxia. A decrease in expression of these metalloproteases was also observed in the model of four-vessel occlusion ischemia in rats with their restoration to the control levels after reperfusion. Preconditioning to mild hypoxia both in the prenatal period and in adults appeared to have a neuroprotective effect restoring, in particular, the levels of amyloid precursor protein, activity of alpha-secretase, and expression of neprilysin and endothelin-converting enzyme to their control values.