Insulin/Insulin receptor modulate APP phosphorylation and dementia

胰岛素/胰岛素受体调节 APP 磷酸化和痴呆

• 批准号: 8310436
• 负责人: LUCIANO D'ADAMIO
• 金额: $ 20.84万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310436
• 关键词: Address; Affect; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Applications Grants; Behavioral; Cognitive; Data; Defect; Dementia; Development; Diabetes Mellitus; Electrophysiology (science); Enzymes; Familial Dementias; Functional disorder; Gene Dosage; Genes; Genotype; Hippocampus (Brain); Human; Impairment; In Vitro; Injection of therapeutic agent; Insulin; Insulin Receptor; Insulin Resistance; Laboratories; Lesion; Light; Link; Measures; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Morphologic artifacts; Mus; Mutate; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Pathology; Patients; Peptides; Phosphorylation; Physiological; Play; Positioning Attribute; Principal Investigator; Protein Dephosphorylation; Protein Fragment; Protein Precursors; Proteins; Proteolysis; Recovery; Risk Factors; Role; Sampling; Senile Plaques; Societies; Stress; Synapses; Synaptic plasticity; Testing; Transgenic Mice; Work; amyloid precursor protein processing; base; design; familial Alzheimer disease; human disease; improved; in vivo; inhibitor/antagonist; mouse model; mutant; presenilin-1; presenilin-2; prevent; synaptic function

DESCRIPTION (provided by applicant): Processing of the amyloid precursor protein (APP) is firmly associated with the pathogenesis of Alzheimer's disease (AD). In fact, mutations in APP itself and in two subunits of an enzyme that regulates APP processing, PSEN1 and PSEN2, cause Familial Alzheimer's disease (FAD). New evidence from our laboratory further stress this link between APP processing and dementia. Familial Danish Dementia (FDD), an AD-like neurodegenerative disorders, is due to mutation in the BRI2/ITM2b gene. Interestingly, BRI2 is an inhibitor of APP processing. The mutations causing FDD results in a loss of BRI2 function and increased processing of APP. Analysis of an animal model of FDD genetically congruous to the human disease (called FDDKI, which, like the human cases, carries one wild-type and one mutant Bri2 allele), shows that the FDD mutation in BRI2 causes impairment in synaptic plasticity and severe hippocampal memory deficits. Recovery from these defects is seen in FDDKI/APP haplodeficient mice. In addition inhibition of APP processing rescues the synaptic deficits of FDDKI mice further connecting APP processing and Familial Danish dementia. Preliminary observations suggest that T668 of APP plays a pivotal role in causing memory loss. In addition, insulin promotes dephosphorylation of this T668 residue, suggesting a mechanism by which insulin can alter AD pathology. Notably, a link between insulin resistance, diabetes mellitus and Alzheimer disease (AD) is supported by several data. Patients with AD often have insulin resistance and insulin improves the cognitive status of patient with early AD. Here, we will further characterize the mechanisms by which insulin alters APP processing and modulates synaptic and hippocampal memory deficits. These studies are likely to shed light on the pathogenesis of AD, as well as to explain the mechanisms by which diabetes and insulin have an effect on AD. PUBLIC HEALTH RELEVANCE: Mutations in genes that regulate the processing of APP cause Familial Dementias in humans. BRI2 is one of these genes. We have generated a mouse model that faithfully represents the human dementias caused by the mutation in BRI2. In this model APP processing is increased and causes memory loss. Given the fact that these mice reproduce accurately the genetic defects of patients, they are ideal to dissect the pathogenic mechanisms that cause dementia in humans. Therefore, this model is suitable for testing therapies for human dementias, including Alzheimer's disease. Diabetes is a widespread condition in our society, and it represents also a risk factor for AD. The studies proposed in this grant application aim to explain how diabetes and insulin have a bearing on the development of AD.

描述（由申请人提供）：淀粉样前体蛋白（APP）的加工与阿尔茨海默病（AD）的发病机制密切相关。事实上，APP本身和调节APP加工的酶的两个亚基PSEN 1和PSEN 2的突变导致家族性阿尔茨海默病（FAD）。我们实验室的新证据进一步强调了APP处理和痴呆症之间的联系。家族性丹麦痴呆（Familial Danish Dementia，FDD）是一种AD样神经退行性疾病，由BRI 2/ITM 2b基因突变引起。有趣的是，BRI 2是APP加工的抑制剂。导致FDD的突变会导致BRI 2功能丧失并增加APP的加工。对遗传上与人类疾病一致的FDD动物模型（称为FDDKI，与人类病例一样，携带一个野生型和一个突变BRI 2等位基因）的分析表明，BRI 2中的FDD突变会导致突触可塑性受损和严重的海马记忆缺陷。在FDDKI/APP单倍缺陷小鼠中观察到从这些缺陷的恢复。此外，APP加工的抑制挽救了FDDKI小鼠的突触缺陷，进一步将APP加工与家族性丹麦痴呆联系起来。初步观察表明，APP的T668在导致记忆丧失中起着关键作用。此外，胰岛素促进该T668残基的去磷酸化，表明胰岛素可以改变AD病理的机制。值得注意的是，胰岛素抵抗，糖尿病和阿尔茨海默病（AD）之间的联系得到了一些数据的支持。AD患者常存在胰岛素抵抗，胰岛素可改善早期AD患者的认知功能。在这里，我们将进一步描述胰岛素改变APP加工和调节突触和海马记忆缺陷的机制。这些研究可能有助于阐明AD的发病机制，并解释糖尿病和胰岛素对AD的影响机制。 公共卫生相关性：调节APP处理的基因突变导致人类家族性痴呆症。BRI 2就是其中之一。我们已经产生了一个小鼠模型，忠实地代表了由BRI 2突变引起的人类痴呆症。在这种模式下，APP处理增加并导致记忆丧失。鉴于这些小鼠准确地复制了患者的遗传缺陷，它们是剖析导致人类痴呆症的致病机制的理想选择。因此，该模型适用于测试人类痴呆症（包括阿尔茨海默病）的疗法。糖尿病是我们社会中的一种普遍疾病，也是AD的一个危险因素。本报告中提出的研究 资助申请旨在解释糖尿病和胰岛素如何对AD的发展产生影响。