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-β peptide (Aβ). In the normally functioning brain Aβ catabolism is regulated by a cohort of proteolytic enzymes including insulin-degrading enzyme (IDE) and their deficit with ageing can result in Aβ 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 Aβ 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.

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This study reports the dynamics of changes in postnatal ontogenesis of the activity of soluble and membrane-bound forms of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the sensorimotor cortex of rats as well as the character of their changes after prenatal hypoxia (Е14, 7% О 2 , 3 hours) or acute hypoxia in adult animals (4 months, 7% О 2 , 3 hours). In normally developing rats the activity of the membrane-bound form of AChE in the sensorimotor cortex gradually increased up to the end of the first month after birth and remained at this high level during all further postnatal ontogenesis while the activity of the soluble form of the enzyme reached its maximum value on the 10th day after birth and decreased significantly by the end of the first month. In animals subjected to prenatal hypoxia the activity both of the soluble and membrane bound forms of AChE during the first two weeks after birth was 20-25% lower compared to controls but increased by the end of the first month and even exceeded the control values and remained increased up to old age (1.5 years). The activity of both forms of BChE in rat sensorimotor cortex at all stages of postnatal ontogenesis was significantly lower than of AChE although the dynamics of their changes was similar to AChE. Prenatal hypoxia led to a decrease in the activity of the membrane-bound form of BChE compared to controls practically at all studied stages of development but was higher at the end of the first month after birth. At the same time, the activity of the soluble form of BChE was decreased only on the 20th day of development compared to the control but increased starting from the end of the first month of life and further. Acute hypoxia in adult rats also led to a decrease in the activity of both forms of AChE and BChE in the sensorimotor cortex but the dynamics of these changes was different. Thus, insufficient oxygen supply to the nervous tissue at different stages of ontogenesis has a significant effect on the activity and ratio of various forms of cholinesterases possessing either growth factor or mediator properties which might lead to the changes in brain development and formation of behavioural reactions including learning and memory аs well as increase the risk of development of the sporadic form of Alzheimer's disease (AD)-one of the most common neurodegenerative diseases of advanced age. This study widening our understanding of the properties of brain cholinesterases under normal and pathological conditions might be useful for developing new approaches towards prevention and treatment of AD.

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