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一个持久原则是识别并预防发病机制的最早步骤。就阿尔茨海默病及其先兆而言，轻度认知障碍损伤（MCI），许多实验室的研究支持尚未证实的假设，即逐渐淀粉样 p 蛋白 (A(3)) 在负责记忆和认知的大脑区域中的积累和寡聚化引发这种复杂的综合症。鉴于学术界和学术界花费了大量资源制药科学家确定抗淀粉样蛋白疗法并将其用于人体试验至关重要准确了解可溶性 A|3 如何开始寡聚以及该过程是否实际上引起 MCI 和早期 AD 中观察到突触功能的微妙损害。在这个新的 RO1 应用程序中，研究人员富有成效地合作发现了低 n A|3 寡聚体的自然分泌细胞培养，然后证明它们抑制长期增强和破坏活体记忆的能力动物现在建议在分子水平上严格定义这些最早的 A(3 组装形式和阐明它们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了敏感的生化方法来分离和研究天然低聚物，我们提出了 4 相互关联的具体目标。 1.确定自然分泌的A|3的精确分子组成通过质谱分析低聚物并寻找共价交联、相关小分子和/或结合蛋白可能有助于其有效的神经元活动。 2. 表征效果天然寡聚物对突触形式和功能的影响，包括在器官型海马培养物中，以及评估它们是否可以诱导 AD 型 tau 磷酸化并改变体内递质释放，3。将天然低聚物纯化至均质，对其进行内在标记并识别其同源分子和活体大脑中的细胞目标。 4. 评估 3 种减少产量的具体治疗策略细胞分泌的寡聚体，从而消除它们的突触毒性：（3-或y-分泌酶抑制剂；某些抗聚集化合物；和伴侣的表情。我们在这方面的研究拥有丰富的经验人类 A(3 寡聚体生理量的无限细胞来源应该使我们能够利用这一点独特的实验范式阐明了最早的 A(3 集会，并伴随着治疗意义。与公共卫生的相关性：因为我们的中央假设是淀粉样蛋白|3-蛋白最早形成的“寡聚体”（双联体、三联体等）是记忆的微妙和渐进性损害是早期 AD 的标志，我们将使用一种独特的方法培养细胞自然产生这种早期形式的实验系统，以便破译这些致病组合的精确性质，确定它们对神经元的损伤机制，并记忆所需的突触，然后用新药物阻断这一过程。

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.