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

2 型糖尿病是阿尔茨海默病的危险因素

• 批准号: 7579116
• 负责人: Jennifer Rodriguez-Rivera
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579116
• 关键词: Adult; Affinity; Aging; Agonist; Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Animal Model; Biochemical; Brain; Calculi; Catabolism; Cognition; Condition; Dementia; Deterioration; Development; Diabetic mouse; Elderly; Enzymes; Exhibits; Functional disorder; Hippocampus (Brain); Hyperinsulinism; Impaired cognition; Individual; Insulin; Insulin Resistance; Insulinase; Link; Memory; Memory impairment; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiological; Play; Population; Proteins; Regulation; Relative (related person); Reporting; Risk; Risk Factors; Role; Synaptic plasticity; Testing; Tg2576; Therapeutic; Wild Type Mouse; age related; base; behavior test; diabetic; enzyme activity; glucose metabolism; insulin sensitivity; interest; mouse model; non-diabetic; prevent; rosiglitazone

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

描述（由申请人提供）：阿尔茨海默氏病是最常见的衰弱型痴呆症。其特点是认知能力下降，特别是在老年人中。这种情况被认为是由于β淀粉样蛋白（Ap）在大脑中的积累，特别是海马体。这种蓄积可能是蛋白质过量产生或清除率降低的结果。2型糖尿病（DM 2）已被报告为AD发展的风险因素。最近的研究表明，DM2中发现的生理条件导致AD风险增加65%。1997年，Kuusisto的研究小组发现，高胰岛素血症（一种与DM2相关的疾病）是非糖尿病个体中AD的危险因素。已发现胰岛素降解酶（IDE）参与Ap的清除。还已知IDE对其另一底物胰岛素具有高亲和力。有趣的是，AD患者在海马体呈现降低的IDE水平。我们认为，高水平的胰岛素，经常发现DM2患者，有反作用IDE导致增加的积累，在大脑中的AP。最近的研究报告了AD小鼠模型Tg2576中的葡萄糖代谢受损。研究指出，与野生型小鼠相比，小鼠中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物酶体增殖物激活受体激动剂（PPAR）（罗格列酮）暴露对小鼠认知功能的影响。罗格列酮是一种药物，可以降低糖尿病小鼠的高胰岛素血症。我们正在对这些老鼠进行行为测试。生物化学表征将确定Ap和胰岛素催化剂中关键酶的活性或水平是否改变。更好地了解DM2和AD之间的相关性将为开发潜在的治疗方法以预防AD患者中发现的生理恶化提供垫脚石