Pathogenic Mechanisms of Cell-Derived Abeta Oligomers

细胞源性 Abeta 寡聚物的致病机制

基本信息

批准号：
8337011
负责人：
DENNIS J SELKOE
金额：
$ 13.57万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8337011
关键词：
Address Alzheimer&apos s Disease Amyloid Animals Binding Proteins Biochemical Biochemistry Biological Brain Brain region Cell Culture System Cell Culture Techniques Cells Cerebrum Chronic Cognition Complex Conditioned Culture Media Cultured Cells Cytopathology Data Dementia Deposition Development Dimerization Equilibrium Gleevec Hippocampus (Brain)Human Impaired cognition Inflammatory Injection of therapeutic agent Injury Label Life Long-Term Potentiation Mass Spectrum Analysis Mediating Memory Memory impairment Methods Microdialysis Microinjections Molecular Molecular Chaperones Molecular Target Mus Nature Neurofibrillary Tangles Neurons Neurotransmitters Non-Steroidal Anti-Inflammatory Agents Pathogenesis Peptides Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Physiological Process Production Property Proteins Protocols documentation Public Health RS-0466 RS0406 Rattus Reporting Research Personnel Resources Role Scientist Series Signal Transduction Source Symptoms Synapses Syndrome System Testing Therapeutic Therapeutic Intervention Triplet Multiple Birth abeta oligomer base cellular targeting crosslink episodic memory impairment experience human disease in vivo inhibitor/antagonist insight meetings mild neurocognitive impairment mutant neurobiological mechanism neurotoxic neurotransmitter release notch protein novel prevent programs secretase small molecule successful intervention synaptic function tau Proteins tau aggregation tau phosphorylation

项目摘要

An enduring principle for successful intervention in human disease is to identify - andthen prevent - the earliest steps in pathogenesis. In the case of Alzheimer's disease and its harbinger, mild cognitive impairment (MCI), studies from many labs support the still unproven hypothesis that the gradual accumulation and oligomerization of amyloid p-protein (A(3)in brain regions serving memory and cognition initiates this complex syndrome. Given the enormous resources being expended by academic and pharmaceutical scientists to identify anti-amyloid therapies and bring them to human trials, it is crucial to understand precisely how soluble A|3begins to oligomerize and whether this process actually induces the subtle compromise of synaptic function seen in MCI and early AD. In this new RO1 application, investigators who have collaborated productively to discover the natural secretion of low-n A|3oligomers in cell culture and then demonstrate their ability to inhibit long-term potentiation and disrupt memory in living animals now propose to rigorously define at the molecular level these earliest A(3assembly forms and elucidate their mechanisms of action on neuronal function. Based on extensive preliminary data and sensitive biochemical methods we have developed to isolate and study natural oligomers, we propose 4 interrelated Specific Aims. 1. Determine the precise molecular composition of naturally secretedA|3 oligomers by mass spectrometry and search for covalent crosslinks, associated small molecules and/or binding proteins that may contribute to their potent neuronal activity. 2. Characterize the effects of the natural oligomers on synaptic form and function, including in organotypic hippocampal cultures, and assess whether they can induce AD-type tau phosphorylation and altered transmitter release in vivo, 3. Purify the natural oligomers to homogeneity, intrinsically label them and identify their cognate molecular and cellular targets in living brain. 4. Assess 3 specific therapeutic strategies to decrease the production of cell-secreted oligomers and thereby abrogate their synaptotoxicity: (3- or y-secretase inhibitors; certain anti-aggregation compounds; and chaperone expression. Our extensive experience in studying this unlimited cellular source of physiological amounts of human A(3 oligomers should enable us to exploit this unique experimental paradigm to elucidate both the nature and the neuronal effects of the earliest A(3 assemblies, with attendant therapeutic implications. Relevance to Public Health: Because our central hypothesis is that the earliest-forming "oligomers" (doublets, triplets, etc.) of amyloid |3-protein underlie the subtle and progressive impairment of memory that is the hallmark of incipient AD, we will use a unique experimental system in which cultured cells naturally produce such early forms in order to decipher the precise nature of these pathogenic assemblies, identify their mechanism of injury on the neurons and synapses required for memory, and then block this process with novel drugs.

成功干预人类疾病的持久原则是确定 - 预防 - 发病机理最早的步骤。就阿尔茨海默氏病及其预兆而温和的认知受损（MCI），来自许多实验室的研究支持了仍然未经证实的假设淀粉样蛋白P蛋白的积累和寡聚（在大脑区域中的A（3）有记忆和认知启动这种复杂综合征。鉴于学术和药物科学家识别抗淀粉样蛋白疗法并将其带入人类试验，这对精确地了解如何溶于a | 3胚才能寡聚，以及此过程是否真的诱导了该过程 MCI和早期AD中看到的突触功能的细微折衷。在这个新的RO1应用程序中有效合作以发现低N a | 3oligomers的自然分泌的调查人员细胞培养，然后证明其抑制长期增强和破坏生活中记忆的能力现在，动物建议在分子水平上进行严格定义这些最早的A（3个组合形式和阐明其对神经元功能的作用机制。基于广泛的初步数据和我们开发的敏感生化方法是为了隔离和研究天然低聚物，我们提出了4 相互关联的特定目标。 1。确定天然分泌的精确分子组成| 3 通过质谱法和寻找共价交联，相关的小分子和/或结合蛋白可能有助于其有效的神经元活性。 2。表征具有突触形式和功能的天然低聚物，包括在器官海马培养物中，评估它们是否可以诱导Ad-Type Tau磷酸化并在体内改变发射机释放，3。将天然寡聚物净到均匀性，本质上标记它们并识别其同源分子和活大脑中的细胞靶标。 4。评估3种特定的治疗策略以减少生产细胞分泌的低聚物，从而消除其突触毒素：（3-或Y-二型酶抑制剂；某些抑制剂；抗聚集化合物；和伴侣表达。我们在研究这个方面的丰富经验无限的人类生理量的人类A（3个低聚物应使我们能够利用这一点独特的实验范式以阐明最早a的性质和神经元效应（3 集会，带有随之而来的治疗意义。与公共卫生有关：因为我们的中央假设是淀粉样蛋白的最早形成的“低聚集者”（双重，三元组等）是微妙而渐进的记忆障碍是初期广告的标志，我们将使用独特的实验系统，其中培养的细胞自然产生这种早期形式，以破译这些病原体组件的精确性质，确定它们在神经元上的损伤机理，并记忆所需的突触，然后用新型药物阻止此过程。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors.

DOI：
10.1523/jneurosci.0203-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
通讯作者：
Selkoe DJ

Aβ oligomers inhibit synapse remodelling necessary for memory consolidation.

DOI：
10.1016/j.neurobiolaging.2010.01.001
发表时间：
2011-12
期刊：
NEUROBIOLOGY OF AGING
影响因子：
4.2
作者：
Freir, Darragh B.;Fedriani, Rocio;Scully, Darren;Smith, Imelda M.;Selkoe, Dennis J.;Walsh, Dominic M.;Regan, Ciaran M.
通讯作者：
Regan, Ciaran M.

Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils.

DOI：
10.1523/jneurosci.3537-10.2010
发表时间：
2010-10-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
O'Nuallain B;Freir DB;Nicoll AJ;Risse E;Ferguson N;Herron CE;Collinge J;Walsh DM
通讯作者：
Walsh DM

A monoclonal antibody against synthetic Aβ dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aβ.

针对合成 Aβ 二聚体组件的单克隆抗体中和脑源性突触可塑性破坏 Aβ。

DOI：
10.1111/j.1471-4159.2011.07389.x
发表时间：
2011
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
O'Nuallain,Brian;Klyubin,Igor;McDonald,JessicaM;Foster,JamesS;Welzel,Alfred;Barry,Andrew;Dykoski,RichardK;Cleary,JamesP;Gebbink,MartijnFBG;Rowan,MichaelJ;Walsh,DominicM
通讯作者：
Walsh,DominicM

Intracerebroventricular Administration of Amyloid β-protein Oligomers Selectively Increases Dorsal Hippocampal Dialysate Glutamate Levels in the Awake Rat.