Pathogenic Mechanisms of Cell-Derived Abeta Oligomers

细胞源性 Abeta 寡聚物的致病机制

• 批准号: 7798985
• 负责人: DENNIS J SELKOE
• 金额: $ 52.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798985
• 关键词: Address; Alzheimer' 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

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——然后预防——疾病