Cerebral Amyloidosis and Dementia

脑淀粉样变性和痴呆

• 批准号: 8668390
• 负责人: JORGE A GHISO
• 金额: $ 34.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668390
• 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.

描述（由申请人提供）：AB 在 AD 发病机制中发挥着核心作用，尽管仍然非常需要充分定义多个 AB 组装体中的哪一个组装体具有神经毒性特性和淀粉样蛋白形成能力。虽然可溶性低聚物比纤维状结构更多地与神经元毒性机制有关，但很少的体内实验和我们自己最近的数据表明，脑内输注可溶性 AD 脑提取物可以加速 APP 转基因小鼠中 AB 淀粉样蛋白形成的接种，但不同聚集状态的同源合成肽则不能加速到相同的程度，这表明 仍然存在未明确的淀粉样变辅因子。两种早发性神经退行性疾病，即家族性英国和丹麦痴呆（FBD 和 FDD），表现出广泛的前淀粉样蛋白和淀粉样蛋白沉积、嗜刚果红性血管病和神经原纤维缠结病理，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，但所有物种都具有很大的寡聚倾向，在脂质双层中组装成离子通道样结构并形成原纤维，所有这些都表明了共同的致病途径。我们假设不相关的肽可能采用类似的改变的淀粉样蛋白形成构型，从而在神经元细胞中引发类似的下游有害影响，当与其他淀粉样蛋白形成辅助因子结合时能够加速体内淀粉样蛋白沉积。因此，我们建议： 目标 1：比较从 FBD / FDD / AD 大脑以及 Tg 小鼠模型中分离出的寡聚和纤维状 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相似组装体的结构要求；目标 2：测试目标 1 中表征的寡聚和纤维状 ABri 和 ADan 物种与类似 AB 结构对其不同神经毒性潜力的功能影响，评估离体和体外范例中特定细胞死亡机制（启动子和效应子 caspase 的激活、线粒体途径、Ca2+ 失调等）的诱导，用组织验证结果 富含寡聚组装体的级分以及在淀粉样蛋白耗尽的组织提取物中重建的合成同系物；目标 3：(a) 在存在/不存在淀粉样蛋白耗尽的脑提取物的情况下，使用海马内注射脑提取物与具有类似寡聚化的合成同源物进行比较，分析 APP 和 ADanPP Tg 动物体内寡聚/原纤维 AB、ABri 和 ADan 物种的外源淀粉样蛋白生成能力，以及 (b) 对 淀粉样蛋白诱导提取物，用于识别常见的翻译后修饰和/或负责淀粉样蛋白诱导活性的其他辅因子。

项目成果

Alzheimer's disease and glaucoma: mechanistic similarities and differences.

• DOI: 10.1097/ijg.0b013e3182934af6
• 发表时间: 2013-06-01
• 期刊: Journal of glaucoma
• 影响因子: 2
• 作者: Ghiso, Jorge A;Doudevski, Ivo;Rostagno, Agueda A
• 通讯作者: Rostagno, Agueda A

Glycosylation of BRI2 on asparagine 170 is involved in its trafficking to the cell surface but not in its processing by furin or ADAM10.

天冬酰胺 170 上的 BRI2 糖基化参与其向细胞表面的运输，但不参与弗林蛋白酶或 ADAM10 的加工。

• DOI: 10.1093/glycob/cwr097
• 发表时间: 2011
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: Tsachaki,Maria;Serlidaki,Despina;Fetani,Andriana;Zarkou,Vasiliki;Rozani,Ismini;Ghiso,Jorge;Efthimiopoulos,Spiros
• 通讯作者: Efthimiopoulos,Spiros

BRI2 interacts with BACE1 and regulates its cellular levels by promoting its degradation and reducing its mRNA levels.

BRI2 与 BACE1 相互作用，并通过促进其降解和降低其 mRNA 水平来调节其细胞水平。

• DOI: 10.2174/1567205011310050009
• 发表时间: 2013
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Tsachaki,Maria;Fotinopoulou,Angeliki;Slavi,Nefeli;Zarkou,Vasiliki;Ghiso,Jorge;Efthimiopoulos,Spiros
• 通讯作者: Efthimiopoulos,Spiros