Molecular Targets of A-beta-Induced Synaptic Dysfunction

A-β 诱导的突触功能障碍的分子靶点

• 批准号: 7090060
• 负责人: MICHAEL D EHLERS
• 金额: $ 27.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090060
• 关键词: Alzheimer' s disease; amyloid proteins; biological signal transduction; cell component structure /function; clathrin; dendrites; embryo /fetus; endocytosis; genetically modified animals; hippocampus; intermolecular interaction; laboratory mouse; laboratory rat; molecular pathology; neural plasticity; neural transmission; neurons; neuropathology; neuroregulation; neurotransmitter receptor; newborn animals; phosphorylation; posttranslational modifications; protein structure function; synapses

DESCRIPTION (provided by applicant): A central goal of research in Alzheimer's disease (AD) is the identification and reversal of the earliest pathological changes in affected brain systems and neural circuits. Although numerous structural and biochemical changes have been documented in late-stage AD brains, the early microscopic events that initiate neuronal dysfunction provide potentially more attractive therapeutic targets. Among the initial targets of AD pathogenesis are neuronal synapses. In its earliest phases, AD is characterized by a remarkably pure impairment of memory that has been attributed to 'subpathological' alterations in excitatory synaptic transmission in the hippocampus. Recent studies strongly support the involvement of misprocessed amyloid precursor protein (APP) and A-beta deposition in the early synaptic and cognitive changes of AD. However, little is known about the molecular mechanisms by which exposure to A-beta affects synaptic plasticity, or potential compensatory mechanisms that could be used to counteract aberrant plasticity. In the proposed research, we will define the molecular targets for A-beta-induced synaptic dysfunction. A newly recognized mechanism for changing synaptic strength is the rapid removal of postsynaptic receptors via endocytosis. We have recently found that dendritic spines contain a zone of clathrin assembly and endocytosis adjacent to, but spatially segregated from, the postsynaptic density. Moreover, we have found that the protein machinery for postsynaptic endocytosis is functionally altered by aging and may be upregulated by exposure to A-beta. These findings present an opportunity to clarify in molecular detail the mechanisms by which A-beta influences excitatory transmission and synaptic plasticity. These studies will provide much-needed insight into the cell biological mechanisms that underlie AD-related changes in synaptic plasticity, and will identify molecular signaling pathways that may correct A-beta-induced changes in synaptic function. As such, the proposed research holds promise for the development of new therapeutic approaches for AD-associated memory loss and cognitive deficit.

描述（由申请人提供）：阿尔茨海默病（AD）研究的中心目标是识别和逆转受影响的大脑系统和神经回路中最早的病理变化。尽管晚期 AD 大脑中存在大量结构和生化变化，但引发神经元功能障碍的早期微观事件提供了潜在的更有吸引力的治疗靶点。 AD 发病机制的最初目标之一是神经元突触。在其早期阶段，AD 的特征是明显的纯粹记忆损伤，这归因于海马兴奋性突触传递的“亚病理性”改变。最近的研究强烈支持错误加工的淀粉样前体蛋白 (APP) 和 A-β 沉积参与 AD 的早期突触和认知变化。然而，人们对 A-β 影响突触可塑性的分子机制或可用于抵消异常可塑性的潜在补偿机制知之甚少。在拟议的研究中，我们将定义 A-β 诱导的突触功能障碍的分子靶点。 一种新认识的改变突触强度的机制是通过内吞作用快速去除突触后受体。我们最近发现树突棘包含一个网格蛋白组装和内吞作用的区域，该区域邻近突触后密度，但在空间上与突触后密度分离。此外，我们发现突触后内吞作用的蛋白质机制会因衰老而发生功能性改变，并且可能因暴露于 A-β 而上调。这些发现为从分子细节上阐明 A-β 影响兴奋性传递和突触可塑性的机制提供了机会。这些研究将为 AD 相关突触可塑性变化的细胞生物学机制提供急需的见解，并将确定可能纠正 A-β 诱导的突触功能变化的分子信号传导途径。因此，拟议的研究有望为 AD 相关记忆丧失和认知缺陷开发新的治疗方法。