Cerebral Amyloidosis and Dementia

脑淀粉样变性和痴呆

• 批准号: 8049051
• 负责人: JORGE A GHISO
• 金额: $ 33.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049051
• 关键词: Abrus; Adopted; Affect; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Model; Apoptotic; Biochemical; Biological; Brain; British; Caspase; Cell Death; Cell Survival; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Clinical; Clinical Trials; Complex; Data; Dementia; Deposition; Development; Disease; Exhibits; Familial Dementias; Familial disease; Genetic; Health; Hippocampus (Brain); Homeostasis; Homologous Gene; Impaired cognition; In Vitro; Individual; Infusion procedures; Inherited; Injection of therapeutic agent; Ion Channel; Length; Lesion; Lipid Bilayers; Lipids; Liquid substance; Mitochondria; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Peptides; Play; Post-Translational Protein Processing; Process; Production; Property; Proteins; Proteomics; Publishing; Role; Structure; Testing; Therapeutic; Time; Tissue Extracts; Tissues; Transgenic Animals; Transgenic Mice; Transgenic Organisms; amyloid formation; amyloid peptide; amyloidogenesis; base; comparative; early onset; familial Alzheimer disease; in vivo; kindred; mitochondrial dysfunction; mouse model; neuron loss; neurotoxic; neurotoxicity; novel; reconstitution; research study; synthetic peptide

DESCRIPTION (provided by applicant): AB plays a central role in AD pathogenesis, although there is still a great need to fully define on which of the multiple AB assemblies underlay the neurotoxic properties and the amyloid-forming ability. While soluble oligomers more than fibrillar structures have been implicated in the mechanism(s) of neuronal toxicity, few in vivo experiments and our own recent data indicate that seeding of AB amyloidogenesis in APP transgenic mice can be accelerated by intracerebral infusion of soluble AD brain extracts but not to the same extent by homologous synthetic peptides in various states of aggregation, suggesting the existence of still undefined amyloidogenic co-factors. Two early-onset neurodegenerative conditions, familial British and Danish dementias (FBD and FDD) show extensive pre-amyloid and amyloid deposits, congophilic angiopathy and neurofibrillary tangle pathology, closely resembling AD. The deposited proteins (ABri in FBD and ADan in FDD), nevertheless, differ from AB in length and in primary structure and yet, all species share great propensity to oligomerize, assemble as ion-channel like structures in lipid bi-layers and form fibrils, all suggestive of common pathogenic pathways. We hypothesize that unrelated peptides could adopt similar altered amyloidogenic configurations that trigger comparable downstream detrimental effects in neuronal cells, being capable of accelerating amyloid deposition in vivo when in conjunction with additional amyloidogenic co-factors. Accordingly, we propose: Aim 1: to compare oligomeric and fibrillar ABri, ADan and AB assemblies isolated from brains with FBD / FDD / AD as well as from Tg mouse models and determine the structural requirements for synthetic ABri, ADan and AB to form in vitro similar assemblies to those found in vivo; Aim 2: to test the functional effect of the oligomeric and fibrillar ABri and ADan species characterized in aim 1 in comparison with analogous AB structures on their differential neurotoxic potential, assessing the induction of specific cell-death mechanisms (activation of initiator and effector caspases, mitochondrial pathways, Ca2+ dysregulation, etc) in ex vivo and in vitro paradigms, validating the results with tissue fractions enriched in oligomeric assemblies as well as synthetic homologues reconstituted in amyloid-depleted tissue extracts; Aim 3: to (a) analyze the exogenous amyloidogenic capability of oligomeric/fibrillar AB, ABri and ADan species in vivo in APP and ADanPP Tg animals using intra-hippocampal injections of brain extracts compared with synthetic homologues with analogous oligomerization in the presence/absence of amyloid-depleted brain extracts and (b) conduct a comparative proteomic analysis of the amyloid-inducing extracts to identify common post-translational modifications and/or additional co-factor(s) responsible for the amyloid-inducing activity. PUBLIC HEALTH RELEVANCE: There is extensive experimental data strongly suggesting that amyloid beta (AB) plays a central role in Alzheimer's disease (AD) although basic questions in the pathogenetic mechanisms remain unclear, particularly the role of oligomers and the existence of amyloidogenic co-factors of the disease. To clarify these issues we propose to study two early-onset non-AB neurodegenerative conditions that closely resemble AD: familial British and Danish dementias. The use of these alternative models of neurodegeneration in close comparison with AD cases will help elucidate whether different amyloids trigger common pathogenic mechanisms and are potentially amenable to similar therapeutics strategies.

描述(由申请人提供)：AB在AD发病机制中发挥核心作用，尽管仍需要充分定义多个AB组件中的哪一个是神经毒性特性和淀粉样蛋白形成能力的基础。虽然可溶性寡聚体比纤维状结构更多地参与了神经元毒性的机制(S)，但很少有体内实验和我们自己的最新数据表明，脑内注射可溶性AD脑提取物可以加速APP转基因小鼠AB淀粉样蛋白的形成，但不同聚集状态的同源合成肽不能同样程度地加速AB淀粉样蛋白的发生，这表明仍存在尚未确定的淀粉样蛋白形成辅助因素。两种早发性神经退行性疾病，英国和丹麦家族性痴呆(FBD和FDD)表现为广泛的淀粉样前和淀粉样沉积，嗜中性血管病变和神经原纤维缠绕病理，与AD非常相似。然而，沉积的蛋白质(FBD中的ABRI和FDD中的Adan)在长度和一级结构上与AB不同，但所有物种都有很大的齐聚倾向，在脂质双层中以离子通道的形式聚集，并形成纤维，所有这些都提示了共同的致病途径。我们假设，不相关的多肽可以采用类似的淀粉样变性构型，在神经细胞中触发类似的下游有害影响，当与其他淀粉样变性辅助因子结合时，能够加速体内淀粉样蛋白的沉积。因此，我们建议：目的1：比较从FBD/FDD/AD和TG小鼠模型脑中分离的ABRI、Adan和AB的寡聚体和纤维状组合物，并确定体外合成的ABRI、Adan和AB形成与体内相似的组合物的结构要求；目的2：比较目标1中的寡聚体和纤维状abri和Adan物种与类似的AB结构对其不同神经毒性潜能的功能影响，评估在体外和体外范例中诱导特定细胞死亡机制(激活启动子和效应者caspase、线粒体通路、钙离子失调等)的作用，并用富含寡聚体组装的组织部分和在去淀粉样蛋白缺失的组织提取液中重组的合成同源物来验证结果；目的：(A)在APP和ADanPP TG动物模型中，通过海马体内注射脑提取物，比较在有/无淀粉样蛋白缺失的脑提取物存在或不存在的情况下，寡聚/纤维状AB、ABRI和Adan物种外源性淀粉样蛋白的形成能力；(B)对淀粉样蛋白诱导提取物进行比较蛋白质组学分析，以确定共同的翻译后修饰和/或与淀粉样蛋白诱导活性相关的附加辅助因子(S)。公共卫生相关性：大量实验数据有力地表明，淀粉样β蛋白(AB)在阿尔茨海默病(AD)中发挥着核心作用，尽管发病机制中的基本问题仍不清楚，特别是寡聚体的作用和引发淀粉样蛋白的疾病辅助因素的存在。为了阐明这些问题，我们建议研究两种与AD非常相似的早发性非AB神经退行性疾病：家族性英国和丹麦痴呆症。使用这些替代的神经变性模型与AD病例进行密切比较，将有助于阐明不同的淀粉样蛋白是否触发共同的致病机制，并潜在地服从于类似的治疗策略。