Diabetes type 2 as a risk factor for Alzheimer's disease

描述(申请人提供)：阿尔茨海默病是最常见的类型的衰弱类型的痴呆症。它的特点是认知能力下降，特别是在老年人口中。这种情况被认为是由于β淀粉样蛋白(AP)在大脑中积累，特别是在海马体。这种积累可能是蛋白质过度生产或清除减少的结果。2型糖尿病(DM2)已被报道为AD发生的危险因素。最近的研究表明，在DM2中发现的生理条件会导致患AD的风险增加65%。1997年，Kuusisto的研究小组表明，高胰岛素血症是非糖尿病患者AD的危险因素，与DM2有关。胰岛素降解酶(IDE)被发现参与AP的清除。我们还知道IDE对它的另一种底物--胰岛素有很高的亲和力。有趣的是，AD患者的海马区IDE水平降低。我们认为，在糖尿病患者中经常发现的高水平胰岛素对IDE有影响，导致AP在大脑中积累增加。最近的研究报道了阿尔茨海默病模型小鼠Tg2576糖代谢受损。研究指出，与野生型小鼠相比，这些小鼠存在外周胰岛素抵抗和高胰岛素血症。基于这些报道，我们有兴趣研究过氧化体增殖物激活受体激动剂(PPAR(罗格列酮))对小鼠认知的影响。罗格列酮是一种可以降低糖尿病小鼠高胰岛素血症的药物。我们正在对这些老鼠进行行为测试。生化特征将决定AP和胰岛素分解代谢中关键酶的活性或水平是否发生改变。更好地了解DM2和AD之间的相关性将为开发预防AD患者生理恶化的潜在治疗方法提供垫脚石

DESCRIPTION (provided by applicant): 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