Role of APP and its Metabolites in Synaptic Degeneration

APP 及其代谢物在突触变性中的作用

• 批准号: 6344246
• 负责人: Lennart Mucke
• 金额: $ 44.5万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344246
• 关键词: Alzheimer's disease; amyloid proteins; behavior test; cognition disorders; confocal scanning microscopy; electrophysiology; enzyme linked immunosorbent assay; genetically modified animals; hippocampus; laboratory mouse; light microscopy; nerve /myelin protein; neural degeneration; neural transmission; platelet derived growth factor; protein structure function; protein tyrosine kinase; statistics /biometry; synapses; synaptophysin; tissue /cell culture; western blottings

Description (Provided by applicant): Neurological diseases that result in the degeneration of synapses culminate in severe cognitive deficits and (behavioral disturbances. These dementing illnesses present increasing medical and socioeconomic problems and raise a wide range of fundamental neuroscientific questions. Alzheimer's disease (AD) is the main cause of age-related dementia and its prevalence is increasing rapidly due to the increasing number of elderly in our population. AD is associated with a prominent degeneration of synapses and with an abnormal accumulation of amyloid beta peptides (AB) in the brain. A-beta is derived from the amyloid protein precursor (APP), which is enriched in synapses. The precise relationship between APP, A-beta, and synaptic loss remains obscure. The current proposal aims to shed light on this relationship. We previously used the platelet-derived growth factor (PDGF) beta chain promoter to express human APP (hAPP) in neurons of transgenic mice. In these studies, we focused on the density of synaptophysin-immunoreactive presynaptic terminals because the loss of these structures correlates well with cognitive decline in AD. High levels of neuronal A-beta production in PDGF-hAPP mice resulted in a decrease of presynaptic terminals and elicited major deficits in synaptic transmission. In Aim 1, we will investigate whether the profile of synaptic protein alterations in PDGF-hAPP mice resembles that in AD brains, affecting some proteins more than others, and we will examine whether these alterations are preceded or followed by changes in pre- or postsynaptic neurons. In Aim 2, we will assess to what extent the development of synaptic, alterations in PDGF-hAPP mice depends on the activity of the protein tyrosine kinase Fyn, ablation of which has been shown to prevent A-beta-induced neurotoxicity in tissue culture. In Aim 3, we will immunize PDGF-hAPP mice, with A-beta to determine whether this approach can induce the clearance of synaptotoxic A-beta species and inhibit synaptic degeneration. In Aim 4, we will investigate the relationship between synaptic alterations and behavioral deficits in PDGF-hAPP mice and determine whether the latter can also be prevented or reversed by A-beta vaccination. Achieving these aims will help assess the potential usefulness of novel therapeutic strategies for this most prevalent neurodegenerative disorder. It will also advance our understanding of the function of synaptic proteins in synapse loss and degeneration, which is the focus of RFA NS-01-002.

描述（由申请人提供）：神经系统疾病，导致 突触的退化最终导致严重的认知缺陷和（行为） 干扰.这些痴呆症目前越来越多的医疗和 社会经济问题，并提出了广泛的基础神经科学 问题.阿尔茨海默病（Alzheimer's disease，AD）是年龄相关性痴呆的主要病因 而且由于越来越多的 老年人在我们的人口。AD与一种显著的 突触和淀粉样β肽（AB）的异常积累， 个脑袋A-β衍生自淀粉样蛋白前体（APP）， 富含突触APP、A-beta和 突触丢失仍然不清楚。目前的建议旨在阐明这一点 关系我们以前使用血小板衍生生长因子（PDGF）β 链启动子在转基因小鼠的神经元中表达人APP（hAPP）。在 在这些研究中，我们着重于突触素免疫反应性的密度， 突触前末梢，因为这些结构的丧失与 认知能力下降PDGF-hAPP中高水平的神经元A-β产生 小鼠导致突触前末梢减少，并引起主要的 突触传递的缺陷。在目标1中，我们将研究 PDGF-hAPP小鼠中突触蛋白改变的特征与AD中相似 大脑，影响某些蛋白质比其他更多，我们将研究是否 这些改变之前或之后是突触前或突触后神经元的变化。 神经元在目标2中，我们将评估突触， PDGF-hAPP小鼠中的改变取决于蛋白酪氨酸的活性 激酶Fyn，其消融已显示可防止A-β诱导的 组织培养中的神经毒性。在目标3中，我们将免疫PDGF-hAPP小鼠， 与A-β，以确定这种方法是否可以诱导清除 突触毒性A-β种类并抑制突触变性。在目标4中， 将研究突触改变和行为之间的关系， 缺陷的PDGF-hAPP小鼠，并确定后者是否也可以 预防或逆转A β疫苗接种。实现这些目标将有助于 评估新的治疗策略的潜在有用性， 神经退行性疾病它也将促进我们对 突触蛋白在突触丧失和变性中的功能， RFA NS-01-002的重点。