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Mechanisms underlying Abeta42-induced neuronal dysfunction and degeneration

Abeta42 诱导神经元功能障碍和变性的机制

基本信息

批准号：
8445259
负责人：
Irwin B Levitan
金额：
$ 25.63万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445259
关键词：
Address Affect Alzheimer&apos s Disease Amino Acids Amyloid Amyloid beta-Protein Behavioral Biological Models Brain CREB1 gene Candidate Disease Gene Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Deposition Drosophila genus Energy Metabolism Eye Gene Expression Profiling Gene-Modified Genes Genetic Genetic Models Genetic Screening Lead Maintenance Memory Metabolism Mitochondria Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Pathogenesis Pathology Pathway interactions Peptides Phosphorylation Play Protein Kinase Role Site Testing Therapeutic Intervention Toxic effect Transgenic Organisms base design fly genetic manipulation genome wide association study hyperphosphorylated tau in vivo insight neurotoxicity novel therapeutic intervention novel therapeutics tau Proteins tau phosphorylation

项目摘要

DESCRIPTION (provided by applicant): Deposits of 42 amino acid amyloid-beta peptide (Abeta42) and hyper-phosphorylated microtubule-associated protein tau in the brain are the pathological hallmarks of Alzheimer's disease (AD). Accumulating evidence suggests that Abeta42 lies upstream of tau in a pathological cascade. However, two critical questions remain elusive. First, how does Abeta42 induce pathological consequences in AD? Second, how does Abeta42 induce abnormal phosphorylation and toxicity of tau? Addressing these questions will advance our understanding of complex AD pathogenesis, and lead to the discovery of novel therapeutic interventions. In this study, Drosophila is used as an efficient genetic model system to unravel molecular mechanism underlying Abeta42-induced toxicity in vivo. Using gene expression profiling and a genome-wide screen, the genes/pathways and chromosomal loci that modify Abeta42-induced neuronal dysfunction were identified. Moreover, co-expression of Abeta42 enhanced phosphorylation and toxicity of tau in fly eyes and brains. Based on these data, we designed our specific aims as follows; Specific Aim 1: To examine the role of and mechanisms underlying reduced cAMP/PKA/CREB activity in Abeta42 toxicity. The cAMP/PKA/CREB pathway plays critical roles in the execution and maintenance of complex brain functions such as memory formation and energy metabolism, and the dysregulation of this pathway has been implicated in the pathogenesis of AD. However, it is not fully understood 1) how Abeta42 affects PKA and CREB activity and 2) whether activation of this pathway protects against Abeta42-induced toxicity in vivo. The relationship of Abeta42 toxicity to dysregulation in the cAMP/PKA/CREB pathway will be analyzed in Abeta42 flies. Specific Aim 2: To elucidate molecular mechanisms underlying toxic interactions between microtubule associated protein tau and Abeta42. Our preliminary data showed that co-expression of A242 and tau enhanced tau-induced toxicity in the eyes and brains of flies, which correlates with increased tau phosphorylation at the AD-related sites S202, T231, and S262. Interestingly, tau phosphorylation at T231 and S262 is known to be upregulated in pretangle neurons in AD brains. Moreover, phosphorylation at S262 has been shown to promote both tau phosphorylation at other sites and tau toxicity. The mechanisms underlying the enhancement of tau phosphorylation and toxicity by Abeta42 will be studied using our fly model as a genetic model system, which may recapitulate an initial step in the abnormal metabolism of tau in AD brains. Specific Aim 3: A search for genes that modify the neuronal dysfunction induced by Abeta42. By a genetic screen, ten chromosomal loci whose haploinsufficiency enhances A2beta2-induced behavioral deficits were identified. The modifier genes in these loci will be identified and characterized. This study will provide mechanistic insights into how Abeta42 induces neurotoxicity and tau pathology in vivo, which will facilitate our understanding of AD pathogenesis and may open novel therapeutic avenues for AD.

描述(申请人提供)：在大脑中沉积42个氨基酸的淀粉样β蛋白(Abeta42)和高度磷酸化的微管相关蛋白tau是阿尔茨海默病(AD)的病理特征。越来越多的证据表明，Abeta42位于tau的上游，呈病理性级联。然而，有两个关键问题仍然难以捉摸。首先，Abeta42是如何导致AD的病理后果的？第二，Abeta42是如何引起tau的异常磷酸化和毒性的？解决这些问题将促进我们对复杂的AD发病机制的理解，并导致新的治疗干预措施的发现。在这项研究中，果蝇被用作一个有效的遗传模型系统来揭示Abeta42在体内诱导毒性的分子机制。利用基因表达谱和全基因组筛选，确定了改变Abeta42诱导的神经元功能障碍的基因/途径和染色体位点。此外，Abeta42的共表达增强了tau在苍蝇眼睛和大脑中的磷酸化和毒性。基于这些数据，我们设计了如下的具体目标：具体目标1：研究cAMP/PKA/CREB活性降低在Abeta42毒性中的作用和机制。CAMP/PKA/CREB通路在记忆形成和能量代谢等复杂脑功能的执行和维持中起着关键作用，该通路的失调参与了AD的发病。然而，1)Abeta42如何影响PKA和CREB活性以及2)激活该途径是否对Abeta42诱导的体内毒性具有保护作用尚不完全清楚。将在Abeta42果蝇中分析Abeta42毒性与cAMP/PKA/CREB途径失调的关系。具体目标2：阐明微管相关蛋白tau和Abeta42之间毒性相互作用的分子机制。我们的初步数据显示，A242和tau的共同表达增强了tau对果蝇眼睛和大脑的毒性，这与AD相关位点S202、T231和S262上tau的磷酸化增加有关。有趣的是，已知T231和S262处的tau磷酸化在AD大脑中的椒盐神经元中上调。此外，S262的磷酸化已经被证明促进了tau在其他位置的磷酸化和tau的毒性。Abeta42增强tau磷酸化和毒性的机制将使用我们的Fly模型作为遗传模型系统来研究，这可能概括了tau在AD大脑中异常代谢的第一步。具体目标3：寻找修改Abeta42诱导的神经元功能障碍的基因。通过遗传筛选，确定了10个单倍体缺陷增强A2beta2诱导的行为缺陷的染色体座位。这些基因座中的修饰基因将被识别和表征。本研究将对Abeta42如何在体内诱导神经毒性和tau病理提供机制方面的见解，这将有助于我们理解AD的发病机制，并可能为AD开辟新的治疗途径。