Insulin/Insulin receptor modulate APP phosphorylation and dementia

描述(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处理的两个亚单位PSEN1和PSEN2的突变会导致家族性阿尔茨海默病(FAD)。来自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这种联系。家族性丹麦痴呆(FDD)是一种类似AD的神经退行性疾病，由BRI2/ITM2b基因突变引起。有趣的是，BRI2是应用程序处理的抑制因素。引起FDD的突变导致BRI2功能丧失和APP处理增加。对一种在基因上与人类疾病一致的FDD动物模型(称为FDDKI，它像人类一样，携带一个野生型和一个突变的Bri2等位基因)的分析表明，BRI2中的FDD突变会导致突触可塑性受损和严重的海马体记忆障碍。在FDDKI/APP单倍体缺陷小鼠中可以看到这些缺陷的恢复。此外，APP处理的抑制挽救了FDDKI小鼠的突触缺陷，进一步将APP处理与家族性丹麦痴呆症联系起来。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T668残基的去磷酸化，提示了胰岛素改变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。阿尔茨海默病患者常有胰岛素抵抗，胰岛素改善早期AD患者的认知状态。在这里，我们将进一步描述胰岛素改变APP处理和调节突触和海马体记忆缺陷的机制。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。

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.