Cerebral Amyloidosis and Dementia

脑淀粉样变性和痴呆

基本信息

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
项目类别：
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&apos 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

项目摘要

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发病机理中起着核心作用，尽管仍然非常需要完全定义哪些多个AB组件的介绍神经毒性特性和淀粉样蛋白形成能力。虽然与原纤维结构相比，与神经元毒性的机制有关，但几乎没有体内实验，但我们自己的最新数据表明，ABS转基因小鼠中AB淀粉样小鼠的播种可以加速溶解性范围，而不是在溶解度上提取的范围，但可以加速溶解度的含量，这些范围的含量是在溶解度上提取的范围，这些范围的含量是溶解性的，而不是在溶解度上提取的含量，而不是在溶解度上提取的范围。仍然存在不确定的淀粉样蛋白生成共同因素。两种早期发作的神经退行性疾病，家族性的英国和丹麦痴呆症（FBD和FDD）表现出广泛的淀粉样蛋白和淀粉样蛋白沉积物，富含血管性血管病和神经纤维缠结病理学，非常类似于AD。但是，沉积的蛋白质（FBD中的ABRI和FDD中的ADAN）与AB的长度和原发性结构不同，但是，所有物种都具有较高的寡聚倾向，以脂质双层和形成原纤维中的结构等离子通道化，所有物种都暗示着常见的病原途径。我们假设无关的肽可以采用类似的改变的淀粉样蛋白生成构型，从而触发神经元细胞中可比的下游有害作用，并且在与其他淀粉样蛋白生成的cocactor结合结合时，能够在体内加速淀粉样蛋白的沉积。因此，我们提出：目标1：比较从具有FBD / FDD / AD的大脑中分离出的寡聚和原纤维ABRI，ADAN和AB组件，以及从TG小鼠模型中分离出来，并确定合成ABRI，ADAN和AB的结构要求，以形成在体内相似的组合中，与在Vivo中发现的相似的组合； 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富含寡聚组件的馏分以及在淀粉样蛋白缺乏的组织提取物中重构的合成同源物； 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淀粉样蛋白诱导提取物，以识别负责淀粉样蛋白诱导活性的常见的翻译后修饰和/或其他co剂。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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