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

描述（由申请人提供）：阿尔茨海默病是痴呆症中最常见的一种。它的特点是认知能力下降，尤其是在老年人中。这种情况被认为是由于大脑中-淀粉样蛋白（Ap）的积累，特别是海马体。这种积累可能是蛋白质生产过剩或清除率降低的结果。2型糖尿病（DM2）已被报道为AD发展的危险因素。最近的研究表明，在DM2中发现的生理状况导致患AD的风险增加65%。1997年，Kuusisto的研究小组发现，与DM2相关的高胰岛素血症是非糖尿病患者患AD的一个危险因素。胰岛素降解酶（IDE）已被发现参与Ap的清除，也知道IDE对其其他底物胰岛素有很高的亲和力。有趣的是，AD患者海马区的IDE水平降低。我们认为，在DM2患者中经常发现的高水平胰岛素对IDE有影响，导致脑内Ap积累增加。最近的研究报道了AD小鼠模型Tg2576的糖代谢受损。研究指出，与野生型小鼠相比，小鼠存在外周胰岛素抵抗和高胰岛素血症。基于这些报道，我们有兴趣研究暴露于过氧化物酶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。生化表征将确定Ap和胰岛素分解代谢的关键酶的活性或水平是否改变。更好地了解DM2与AD之间的相关性，将为开发潜在的治疗方法以预防AD患者的生理恶化提供基石

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