Mechanisms of synapse dysfunction in Alzheimer's disease

阿尔茨海默病突触功能障碍的机制

• 批准号: 7911479
• 负责人: JANE M SULLIVAN
• 金额: $ 9.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7911479
• 关键词: AMPA Receptors; Action Potentials; Acute; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Binding; Biochemical; Biolistics; Biological Assay; Biological Models; Bypass; Calcium; Caspase; Cell surface; Cells; Chimeric Proteins; Cleaved cell; Cognitive deficits; Complement; Data; Development; Disease Progression; Dyes; Enzymes; Excision; Excitatory Synapse; Fire - disasters; Fluorescent Dyes; Functional disorder; Hippocampus (Brain); Imaging Techniques; Inherited; Insulin; Insulin Receptor; Knock-in Mouse; Knockout Mice; Knowledge; Ligands; Link; Long-Term Depression; Measurement; Mediating; Metabotropic Glutamate Receptors; Molecular; Molecular Target; Monitor; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neuraxis; Neurons; Neurotransmitters; Nicotinic Receptors; Pathway interactions; Patients; Positioning Attribute; Preparation; Presenile Alzheimer Dementia; Presynaptic Terminals; Production; Protein Isoforms; Protein Overexpression; Proteins; Proteolysis; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Slice; Staging; Surface; Symptoms; Synapses; Synaptic Transmission; System; Testing; Transfection; Transgenic Model; Variant; Viral; aged; cognitive function; depressed; depression; design and construction; experience; familial Alzheimer disease; follow-up; improved; monomer; mutant; neurotransmission; new therapeutic target; novel; optical imaging; overexpression; peptide A; postsynaptic; presenilin; presynaptic; prevent; receptor; research study; secretase; theories; therapy development; transmission process; voltage clamp

DESCRIPTION (provided by applicant): A prominent theory about Alzheimer's disease (AD) proposes that early cognitive deficits are due to subtle alterations in synaptic transmission, but specific AD-related changes in synaptic transmission are not well understood. In order to better understand the role of synaptic deficits during the early stages of AD, we must study the effects of AD-related proteins on synaptic transmission in a mammalian central nervous system preparation. Two proteins that have been strongly implicated in AD-related synaptic dysfunction are amyloid precursor protein (APP) and presenilin. We have recently shown that overexpression of APP depresses synaptic transmission through both pre- and postsynaptic mechanisms, and that this depression depends on production of amyloid beta peptide (A?). It remains to be determined which specific isoform of A? (A?40 or A?42) is the relevant ligand, and which surface receptors (if any) is responsible mediating its effects. Presenilin is a critical component of ?-secretase, an enzyme required for A? production. Presenilin is also known to influence storage and release of calcium from internal stores. Changes in the levels of intracellular calcium are a critical signal for many pathways inside the cell, including signals that tell neurons how much neurotransmitter to release when they fire an action potential. Thus, changes in presenilin levels or function could affect synaptic transmission by altering either A? production or intracellular calcium levels. Our long-term objective is to develop a model system that will allow us to investigate the molecules and signaling pathways that are responsible for synaptic dysfunction underlying cognitive deficits associated with AD. We will focus initially on PS1 and APP. Specific Aim 1 of this proposal is to identify the role of wild-type PS1 in synaptic transmission and test the hypothesis that expression of Familial AD-linked mutant PS1 alters synaptic transmission. Specific Aim 2a is to determine whether elevated levels of secreted A?42 depress transmission at excitatory synapses, and whether either A240 or the caspase cleavage-resistant mutant APPD664A can reduce this depression. Specific Aim 2b is to identify the role of nicotinic acetylcholine receptors, NMDA receptors, group I metabotropic glutamate receptors, and insulin receptors in APP-mediated depression of synaptic transmission. Our experimental strategy is to use electrophysiological and optical imaging techniques to identify specific changes in neurotransmission produced by virally-mediated overexpression of wild-type and mutant forms of presenilin, APP, and APP-cleavage products in cultured mouse hippocampal neurons. Our lab has extensive experience studying the effects of virally-mediated overexpression of a variety of proteins on synaptic transmission in cultured hippocampal neurons, and is, therefore, in an excellent position to exploit this system to identify the effects of AD-related proteins on neurotransmission. These studies will provide molecular targets for novel therapies to improve cognitive function and delay further neurodegeneration in patients with early Alzheimer's disease. Alzheimer's disease is the most common cause of cognitive deficits in the aged, and is thought to begin with synaptic dysfunction. Understanding the cellular and molecular mechanisms underlying this synaptic dysfunction will provide new targets for therapeutic treatments to relieve symptoms, and slow or perhaps even stop disease progression.

描述（由申请人提供）：关于阿尔茨海默氏病（AD）的一个突出理论提出，早期的认知缺陷是由于突触传播的细微变化所致，但突触传播的特定特定变化尚不清楚。为了更好地了解AD早期突触缺陷的作用，我们必须研究与AD相关蛋白在哺乳动物中枢神经系统制备中的突触传播的影响。两种与AD相关的突触功能障碍非常重要的蛋白质是淀粉样蛋白前体蛋白（APP）和Presenilin。我们最近表明，APP的过表达通过突触前和突触后机制降低突触传播，并且这种抑郁症取决于淀粉样蛋白β肽的产生（A？）。还有待确定哪种特异性同工型？ （A？40或A？42）是相关的配体，哪些表面受体（如果有）负责介导其效果。 PRESENILIN是？分泌酶的关键成分，是A所需的酶？生产。众所周知，Presenilin也会影响内部商店中钙的储存和释放。细胞内钙水平的变化是细胞内许多途径的关键信号，其中包括告诉神经元在发射动作电位时释放多少神经递质的信号。因此，老年蛋白水平或功能的变化可能会通过改变任何一个来影响突触传播？生产或细胞内钙水平。我们的长期目标是开发一个模型系统，该系统将使我们能够研究负责与AD相关的认知缺陷的突触功能障碍的分子和信号通路。我们最初将专注于PS1和应用。该提案的具体目的1是确定野生型PS1在突触传播中的作用，并检验以下假设：家族广告连接突变体PS1的表达会改变突触传播。具体目标2a是确定兴奋性突触时分泌的A级下降升高水平是否升高，以及A240还是caspase裂解的抗性突变体APPD664A是否可以减少这种抑郁症。具体目标2B是确定烟碱乙酰胆碱受体，NMDA受体，I组代谢型谷氨酸受体和胰岛素受体在APP介导的突触传播抑郁症中的作用。我们的实验策略是使用电生理和光学成像技术来识别由野生型和突变体形式的Presenilin，App和App-cleavage产物在培养的小鼠海马神经元中的野生型和突变形式的过表达产生的特定变化。我们的实验室拥有丰富的经验，研究了各种蛋白质的病毒介导的过表达对培养的海马神经元突触传播的过表达，因此，可以利用该系统来识别AD相关蛋白对神经递质的影响。这些研究将为新疗法提供分子靶标，以改善认知功能并延迟早期阿尔茨海默氏病患者的进一步神经退行性。阿尔茨海默氏病是老年人认知缺陷的最常见原因，被认为始于突触功能障碍。了解这种突触功能障碍的细胞和分子机制将为治疗治疗以缓解症状，并缓慢甚至可以阻止疾病进展。