Investigating a positive biological role for the A Beta peptide

研究 A Beta 肽的积极生物学作用

• 批准号: 9809520
• 负责人: THOMAS A JONGENS
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809520
• 关键词: Abeta synthesis; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Area; Attention; Basic Science; Binding; Biological; Biology; Brain; CRISPR/Cas technology; Cause of Death; Cleaved cell; Clinical; Clinical Trials; Complex; Dementia; Development; Diagnosis; Disease; Disease Progression; Disease model; Drosophila genus; Equilibrium; Etiology; Event; Failure; Future; Genes; Genetic; Genetic Diseases; Glucose; Goals; High Prevalence; Hippocampus (Brain); Histopathology; Human; Impaired cognition; In Vitro; Insulin; Insulin Receptor; Insulin Resistance; Insulinase; Light; Link; Memory; Memory Loss; Metabolic; Metabolic Diseases; Modeling; Mutation; Nature; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathogenesis; Pathogenicity; Pathology; Patients; Peptides; Physiological; Play; Publications; Regulation; Research; Risk Factors; Role; Techniques; Testing; United States; Work; amyloid precursor protein processing; base; cost; design; experimental study; familial Alzheimer disease; fly; gamma secretase; high risk; in vivo; insulin signaling; neurotoxic; novel; presenilin; preservation; prevent; protein expression; reduce symptoms; side effect; symptom treatment; tool

Abstract Despite a century of research and countless clinical trials, Alzheimer's Disease (AD) etiology is still poorly understood and treatment options are incredibly limited. The histopathology of the disorder, has generally focused on the accumulation of neurotoxic plaques in the brain which are composed of the Aβ peptide, a cleavage product of the Amyloid Precursor Protein (APP). This peptide has received much attention in the AD field due to its role in Familial Alzheimer's Disease (FAD), a genetic form of the disease with rapid but similar disease progression. Importantly, FAD is caused by the autosomal dominant inheritance of mutations, in APP and the presenilin genes. This is significant because presenilin is the catalytic component of the γ-secretase complex that cleaves APP, releasing Aβ. Since anti-amyloidogenic and anti-γ-secretase agents have been largely ineffective in treating AD, and often even seem to worsen the condition in AD patients, alternative mechanisms need to be considered. One such mechanism is altered insulin signaling. There are significant links between AD and Type II diabetes (T2D), and signs of altered insulin resistance have been identified in the brains of AD patients. This is important as insulin signaling also plays a role in memory formation. We believe that these two distinct areas of AD research may actually be closely linked. We believe that it is irrefutable that Aβ plays a pivotal role in AD pathogenesis, however we also believe that this role has not been fully illustrated. It has been suggested in select publications that Aβ competes with insulin for binding to both the insulin receptor and the insulin degrading enzyme. We believe that this activity is responsible for regulating insulin signaling in the brain. When Aβ levels are altered, insulin signaling may proceed unregulated resulting in brain insulin resistance with age, as occurs in the periphery of T2D patients. Our hypothesis is that Aβ plays a positive biological role in insulin signaling regulation, and that this regulation is altered in AD. To test this hypothesis, we will generate animal models that expresses both Aβ and insulin at physiologically accurate levels. In Aim 1, we propose to use the newly developed CRISPR technology to generate a physiologically relevant fly model of FAD. In Aim 2, we will use in vitro techniques to test the concept that Aβ and insulin work in tandem to modulate insulin signaling levels. Finally, in Aim 3, we will use the new FAD fly model to determine if Aβ is required in the brain to regulate insulin signaling, and if this balance is altered in AD. Upon conclusion of the experiments proposed, we will have determined if Aβ plays a positive biological role in the regulation of insulin signaling, and if alterations in this regulatory role may contribute to AD pathogenesis. Further, we will have developed a new, physiologically accurate fly model of AD which will be an invaluable tool in both our future studies and in the work of other groups investigating the cause of this devastating disorder.

摘要 尽管经过世纪的研究和无数的临床试验，阿尔茨海默病（AD）的病因学仍然很差 了解和治疗选择是非常有限的。该疾病的组织病理学通常 集中于脑内神经毒性斑块的积累，这些斑块由Aβ肽、 淀粉样前体蛋白（APP）的裂解产物。这种肽在AD中备受关注 由于其在家族性阿尔茨海默病（FAD）中的作用，FAD是一种遗传形式的疾病， 疾病进展。重要的是，FAD是由APP中的常染色体显性遗传突变引起的， 和早老素基因。这是有意义的，因为早老素是γ-分泌酶的催化组分 复合物切割APP，释放Aβ。 由于抗淀粉样蛋白生成剂和抗γ-分泌酶剂在治疗AD方面基本无效， 通常甚至似乎使AD患者的病情恶化，需要考虑替代机制。一 这种机制是改变的胰岛素信号传导。AD和II型糖尿病之间存在显著联系 (T2D)并且在AD患者的大脑中已经确定了改变的胰岛素抵抗的迹象。这是 重要的是胰岛素信号也在记忆形成中发挥作用。 我们认为，这两个不同的AD研究领域实际上可能是密切相关的。我们认为 Aβ在AD发病机制中起关键作用是无可辩驳的，然而我们也认为这种作用还没有被证实。 充分说明。在选定的出版物中提出，Aβ与胰岛素竞争结合两者 胰岛素受体和胰岛素降解酶。我们认为，这项活动是负责调节 大脑中的胰岛素信号。当Aβ水平改变时，胰岛素信号传导可能不受调节， 随着年龄的增长，大脑胰岛素抵抗，如发生在T2 D患者的外周。 我们的假设是，Aβ在胰岛素信号调节中起着积极的生物学作用， 在AD中调节改变。为了验证这一假设，我们将建立同时表达Aβ和 生理上准确的胰岛素水平。在目标1中，我们建议使用新开发的CRISPR 技术来产生FAD生理相关的飞行模型。在目标2中，我们将使用体外技术， 测试Aβ和胰岛素协同作用调节胰岛素信号水平的概念。在目标3中，我们 将使用新的FAD苍蝇模型来确定大脑中是否需要Aβ来调节胰岛素信号，以及如果这 在AD中改变平衡。在所提出的实验结束时，我们将确定Aβ是否起作用。 积极的生物学作用的调节胰岛素信号，如果改变这种调节作用， 有助于AD发病机制。此外，我们将开发一种新的，生理上准确的苍蝇模型， 这将是我们未来研究和其他研究小组工作的宝贵工具。 导致这种毁灭性的疾病。