Cerebral Amyloidosis and Dementia

脑淀粉样变性和痴呆

• 批准号: 8414469
• 负责人: JORGE A GHISO
• 金额: $ 6.84万
• 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/8414469
• 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发病机制中起核心作用，尽管仍然非常需要完全确定多种AB组装体中的哪一种具有神经毒性性质和淀粉样蛋白形成能力。虽然可溶性寡聚体比纤维状结构更多地涉及神经元毒性的机制，但很少有体内实验和我们自己最近的数据表明，在APP转基因小鼠中接种AB淀粉样蛋白生成可以通过脑内输注可溶性AD脑提取物来加速，但不同聚集状态的同源合成肽的作用程度不同，提示存在尚未确定的淀粉样蛋白生成辅因子。两种早发性神经退行性疾病，家族性英国和丹麦痴呆（FBD和FDD）显示广泛的前淀粉样蛋白和淀粉样蛋白沉积，嗜酸性血管病和神经系统缠结病理学，非常类似于AD。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，然而，所有物种都具有很大的寡聚化倾向，在脂质双层中组装为离子通道样结构并形成原纤维，所有这些都提示共同的致病途径。我们假设，不相关的肽可以采取类似的改变淀粉样蛋白的配置，触发类似的下游有害影响的神经元细胞，能够加速淀粉样蛋白沉积在体内时，与其他淀粉样蛋白辅助因子。因此，我们提议：目标1：比较从具有FBD / FDD / AD的脑以及从Tg小鼠模型中分离的寡聚和纤维状ABri、ADan和AB组装体，并确定合成ABri、ADan和AB在体外形成与体内发现的组装体相似的组装体的结构要求;目的2：测试目的1中表征的寡聚和纤维状ABri和ADan物质与类似AB结构相比的功能效果其差异神经毒性潜力，评估特定细胞死亡机制的诱导（启动子和效应子半胱天冬酶的激活、线粒体途径、Ca 2+失调等），验证富含寡聚体组装体的组织级分以及在淀粉样蛋白耗尽的组织提取物中重构的合成同系物的结果;目的3：为了（a）分析寡聚体/纤维状AB的外源性淀粉样蛋白生成能力，在存在/不存在淀粉样蛋白耗尽的脑提取物的情况下，使用脑提取物的海马内注射的APP和ADanPP Tg动物中的体内ABri和ADan种类与具有类似寡聚化的合成同系物相比，以及（B）对淀粉样蛋白诱导提取物进行比较蛋白质组学分析，以鉴定负责淀粉样蛋白诱导活性的常见翻译后修饰和/或其他辅因子。公共卫生关系：大量的实验数据强烈表明淀粉样蛋白β（AB）在阿尔茨海默病（AD）中起着核心作用，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淀粉样蛋白生成辅助因子的存在。为了澄清这些问题，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。与AD病例密切比较，使用这些替代的神经变性模型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，并可能适用于类似的治疗策略。