Role of VAMP1 in synaptic transmission and Alzheimer's dementia

VAMP1 在突触传递和阿尔茨海默氏痴呆中的作用

• 批准号: 10227451
• 负责人: Ferenc Deak
• 金额: $ 29.56万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10227451
• 关键词: Abeta synthesis; Action Potentials; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Brain; C-terminal; Cell physiology; Cognition; Complex; Couples; Coupling; Data; Dementia; Development; Diagnosis; Disease; Disease Progression; Elderly; Electrodes; Electrophysiology (science); Elements; Endocytosis; Endocytosis Pathway; Etiology; Exocytosis; Fluorescence Microscopy; Functional disorder; Generations; Genes; Genetic; Genetic Screening; Goals; Healthcare; Heterozygote; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Human Genetics; Impaired cognition; Knockout Mice; Knowledge; Laboratories; Late Onset Alzheimer Disease; Learning; Link; Membrane Proteins; Memory; Methods; Mission; Modeling; Molecular; Mus; Mutation; N-terminal; Nerve Degeneration; Neurons; Neurotransmitters; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phase; Predisposition; Production; Protein Isoforms; Proteins; Reporting; Research; Role; SNAP receptor; Sampling; Senile Plaques; Series; Severities; Single Nucleotide Polymorphism; Societies; Source; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; System; Testing; Tg2576; Transgenic Mice; United States; United States National Institutes of Health; VAMP-1; Variant; Vesicle; age group; aging population; amyloid formation; amyloid precursor protein processing; amyloidogenesis; base; disability; effective therapy; experimental study; in vivo; innovation; insight; member; molecular targeted therapies; mouse model; mutant; neurotransmission; novel; null mutation; older patient; overexpression; patch clamp; preservation; prevent; protective effect; public health relevance; receptor; synaptic failure; synaptic function; vesicle-associated membrane protein; vesicular release

Abstract Alzheimer’s disease (AD) is a major cause of dementia, affecting millions of elderly patients in our aging society, and thus represents a severe health care challenge. Currently available drugs may provide some temporary relief but none of them is able to halt disease progression or cure. To develop better therapies a clear understanding of the disease etiology is urgently needed. Recent data suggest the rate of synaptic activity and particularly rate of vesicle endocytosis is critically important for the processing of amyloid precursor protein (APP) into beta-amyloid (Abeta), a source of major toxic component in AD. The exact molecular mechanism connecting synaptic transmission to APP processing is still unknown. My laboratory’s long-term goal is to identify new, molecular therapeutic target(s) in the brain that can help to prevent synaptic dysfunction and neurodegeneration to preserve cognition and memory. The objective in this application is to examine a specific class of proteins – the vesicular membrane associated proteins (VAMPs/synaptobrevins) and their role in synaptic release and Abeta production. Our strong preliminary results establish synaptobrevin1/VAMP1 (syb1), a member of the SNARE (SNAP Receptor) complex, as a novel object for this innovative research of dementia: a) in human genetic screens single nucleotide polymorphism (SNP) variants of the VAMP1 gene encoding syb1 are significantly associated with late onset AD; b) SNPs associated with increased expression of VAMP1 increase the risk of AD and SNPs associated with lower VAMP1 expression reduces the risk of AD; c) in the new VAMP1 KO mice endogenous Abeta40 and Abeta42 levels are substantially reduced. Based on these observations, the central hypothesis is that VAMP1 is a key coupling protein between vesicular release and APP processing. We hypothesize that variations in VAMP1 level alter the coupling of synaptic transmission to APP processing and therefore have profound effect on Abeta production. The rationale for the proposed research is that understanding the molecular mechanism that activates Abeta production will provide a novel, better way to lower Abeta levels and it may prevent or delay cognitive decline in AD patients. We will test this hypothesis by pursuing three specific aims: 1) Examine the effect of synaptobrevin expression level on synaptic activity and Abeta production in neurons using the novel VAMP1 KO mice. 2) Identify the structural elements of VAMP1 coupling synaptic activity to amyloidogenic pathway of APP processing. 3) Evaluate the effects of reduced VAMP1 levels on preventing cognitive impairment in the AD model Tg2576 mice in vivo. These aims will be tested through extensive analysis of synaptic activity, endocytosis and Abeta production with sophisticated methods including multi-electrode and patch-clamp electrophysiology and live fluorescence microscopy. The proposed research is significant because it has the potential to identify VAMP1 as the first synaptic regulator of amyloidogenesis and novel target for AD diagnosis and therapy.

抽象的 阿尔茨海默病 (AD) 是导致痴呆症的主要原因，影响着数百万老年患者 社会，因此构成了严峻的医疗保健挑战，目前可用的药物可能会提供一些帮助。 暂时缓解，但没有一个能够阻止疾病进展或治愈。 迫切需要清楚地了解该疾病的病因，最近的数据表明突触发生率。 活性，特别是囊泡内吞作用的速率对于淀粉样蛋白前体的加工至关重要 蛋白质 (APP) 转化为 β-淀粉样蛋白 (Abeta)，这是 AD 中主要毒性成分的来源。 我的实验室的长期研究将突触传递与 APP 处理联系起来的机制仍然未知。 目标是确定大脑中新的分子治疗靶点，有助于预防突触功能障碍 和神经退行性变以保留认知和记忆。 特定类别的蛋白质 – 囊泡膜相关蛋白（VAMP/突触短蛋白）及其作用 我们强有力的初步结果证实了 synaptobrevin1/VAMP1。 (syb1)，SNARE（SNAP 受体）复合体的成员，作为这项创新研究的新对象 痴呆症：a) 人类基因筛查中 VAMP1 基因的单核苷酸多态性 (SNP) 变体 编码 syb1 与迟发性 AD 显着相关 b) 与表达增加相关的 SNP； VAMP1 表达增加会增加 AD 风险，而与 VAMP1 表达较低相关的 SNP 会降低 AD 风险； c) 在新的VAMP1 KO小鼠中内源性Abeta40和Abeta42水平大幅降低。 这些观察结果的中心假设是VAMP1是囊泡释放之间的关键偶联蛋白 我们发现 VAMP1 水平的变化会改变突触的耦合。 传输到APP处理，因此对Abeta生产产生深远影响。 拟议的研究是，了解激活 Abeta 产生的分子机制将提供 一种降低 Abeta 水平的新方法，它可以预防或延缓 AD 患者的认知能力下降。 通过追求三个具体目标来检验这一假设：1）检查突触短蛋白表达水平对 使用新型 VAMP1 KO 小鼠观察神经元的突触活性和 Abeta 产生 2) 识别结构。 VAMP1 的元件将突触活性与 APP 加工的淀粉样蛋白生成途径耦合。 降低 VAMP1 水平对预防 AD 模型 Tg2576 小鼠体内认知障碍的影响。 这些目标将通过分析突触活性、内吞作用和 Abeta 产生进行广泛测试 采用复杂的方法，包括多电极和膜片钳电生理学以及活体荧光 所提出的研究具有重要意义，因为它有可能将 VAMP1 识别为第一个。 淀粉样蛋白生成的突触调节因子和 AD 诊断和治疗的新靶点。