Alzheimers Disease Mechanism & Experimental Therapeutic

阿尔茨海默病发病机制

• 批准号: 7591027
• 负责人: PHILIP C WONG
• 金额: $ 99.51万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591027
• 关键词: Alzheimers; Disease; Mechanism; Experimental; Therapeutic

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common cause of dementia of the elderly, is a progressive neurodegenerative disorder characterized by the deposition of amyloid-beta (Abeta) and neurofibrillary tangles in the brain. Endoproteolytic cleavages of APP by beta-and gamma-secretases result in the generation of Abeta peptides. The exciting discoveries of beta-secretase and components of the gamma-secretase complex over the past several years provided opportunities to examine the physiological roles of BACE1 and Nicastrin (NCT) and to evaluate these proteins as therapeutic targets for AD. We created BACE1 null mice and demonstrated that BACE1 is the principal beta-secretase necessary to cleave APR to generate Abeta. In addition, we generated NCT null (NCT-/-) mice and NCT-/- cells and established that NCT is an integral member of the gamma-secretase complex. Taking advantage of our multidisciplinary group of talented investigators, we plan to extend our beta and gamma-secretase program to address several key issues outlined in the following Aims: 1) To determine whether deficits in synaptic functions or cognitive performance occur in BACE1-/-, BACE2-/-, or BACE1-/-;BACE2-/- mice; 2) To develop a conditional tet-inducible BACE1 transgenic model to prospectively address the reversibility of Abeta induced abnormalities and the capacity of the brain to repair itself; 3) To determine whether Abeta burden can be reduced in brains of mutant PS1;APP mice by genetically modulating the levels of BACE1 and/or components of the gamma-secretase complex; 4) To test the hypothesis that Aph-1 and NCT are required to regulate the stability of each other to form a stable pre-complex for assembly of PS and Pen-2. In such a model, we suggest that the three mammalian Aph-1 homologues (Aph-1aL, Aph-1aS and Aph-1b) define a set of six distinct functional gamma-secretase complexes; 5) To determine physiological role of NCT during post-natal development, maturation, and aging outside the central nervous system, NCT transgenic mice will be generated, characterized and crossbred to NCT-/- mice to complement the developmental defects in NCT-/- mice, and 6) To determine the roles of Aph-1a and Aph-1b by generation and characterization of mice and cells deficient in these components of the gamma-secretase complex. In concert, the Projects in this proposal are designed not only to examine the roles of BACE1, BACE2, and components of the gamma-secretase complex, but also allow a critical evaluation of these proteins as therapeutic targets in efforts to ameliorate Abeta amyloidosis in individuals with AD. PROJECT 1 P.I.: Donald L. Price, M.D. Title: BACE1 and BACE2 in Cognition and Models of Aa Amyloidosis Description (provided by applicant) With the discovery of BACE1 as the a-secretase involved in the generation of a-amyloid (Aa) peptides in Alzheimer's disease (AD), we embarked on a series of studies to examine the functional roles of this transmembrane aspartyl protease. We have provided evidence to support our hypothesis that the distributions and levels of BACE1 and BACE2, along with APR, are key determinants of selective vulnerability of brain to Aa amyloidosis. Importantly, deletion of BACE1 abolished Aa deposition and prevented cognitive deficits occurring in brains of mutant APP;PS1 mice. Although BACE1 null mice do not exhibit overt developmental abnormalities, our recent studies show that these animals do manifest alterations in performance on tests of cognition and emotion. The goal of Project 1 is to assess the functional roles of BACE1 and BACE2 and to evaluate critically BACE1 as a high priority therapeutic target for treatment of AD. Thus, studies in Aim 1 are designed to examine whether deficits in synaptic functions or cognitive/behavioral abnormalities occur in BACE1-l-, BACE2-l-, or BACE1-l- , BACE2-l- mice. In Aim 2, we plan to examine the link between abnormal accumulations of Aa peptides and synaptic abnormalities occurring in APPswe;PSl?E9 mice. These studies are critical for Aim 3, which are designed to assess the degree of reversibility/recovery following experimental reductions of BACE1 at different stages of Aa amyloidosis and degeneration. We anticipate that novel mechanism-based treatments such as BACE1 inhibitors will become available in the future, and it is therefore important to prospectively address the issues of the reversibility of Aa induced abnormalities and the capacity of the brain to repair itself. Investigations in Aim 3 are designed to determine to what extent Aa deposition and associated abnormalities can be reversed following reduction of BACE1 activity at various times after the initiation of Aa deposition. Taken together, results from these studies will provide important information regarding the physiological roles of BACE1 and BACE2 and allow a critical evaluation of BACE1 as a therapeutic target in efforts to reduce Aa burden in individuals with AD. Furthermore, these studies provide important information regarding potential mechanism based toxicities associated with anti-BACE1 therapy in humans that should be carefully monitored in clinical trials in the future.

描述（由申请人提供）： 阿尔茨海默病（Alzheimer's disease，AD）是老年人痴呆的最常见原因，是一种进行性神经退行性疾病，其特征在于淀粉样蛋白β（Amyloid-beta，Abeta）和神经元缠结在脑中的沉积。β-和γ-分泌酶对APP的内切蛋白水解裂解导致Abeta肽的产生。在过去的几年中，β-分泌酶和γ-分泌酶复合物组分的令人兴奋的发现提供了研究BACE 1和Nicastrin（NCT）的生理作用并评估这些蛋白质作为AD治疗靶点的机会。我们创建了BACE 1基因敲除小鼠，并证明BACE 1是切割APR产生Abeta所需的主要β-分泌酶。此外，我们产生了NCT null（NCT-/-）小鼠和NCT-/-细胞，并确定NCT是γ-分泌酶复合物的组成成员。利用我们多学科的天才研究小组，我们计划扩展我们的β和γ分泌酶计划，以解决以下目标中概述的几个关键问题：1）确定BACE 1-/-，BACE 2-/-或BACE 1-/-; BACE 2-/-小鼠中是否发生突触功能或认知能力的缺陷; 2）开发条件性tet诱导的BACE 1转基因模型，以前瞻性地解决Abeta诱导的异常的可逆性和脑自身修复的能力; 3）确定Abeta负荷是否可以在突变型PS1的脑中减少;通过遗传调节BACE 1和/或γ-分泌酶复合物的组分的水平来对APP小鼠进行免疫调节; 4）测试Aph-1和NCT需要调节彼此的稳定性以形成稳定的前复合物用于PS和Pen-2的组装的假设。在这样的模型中，我们认为三种哺乳动物Aph-1同源物（Aph-1aL、Aph-1aS和Aph-1b）定义了一组六种不同的功能性γ-分泌酶复合物; 5）为了确定NCT在中枢神经系统外的出生后发育、成熟和衰老期间的生理作用，将产生NCT转基因小鼠，表征并与NCT-/-小鼠杂交以补充NCT-/-小鼠中的发育缺陷，和6）通过产生和表征缺乏γ-半乳糖苷酶的这些组分的小鼠和细胞来确定Aph-1a和Aph-1b的作用。分泌酶复合物与此同时，该提案中的项目不仅旨在研究BACE 1，BACE 2和γ-分泌酶复合物组分的作用，而且还允许对这些蛋白质作为治疗靶点进行关键评价，以改善AD患者的Abeta淀粉样变性。 项目1 P.I.： Donald L.普莱斯，医学博士 职务名称： BACE 1和BACE 2在Aa型淀粉样变性认知和模型中的作用 说明（申请人提供） 随着BACE 1作为α-分泌酶参与阿尔茨海默病（AD）中α-淀粉样蛋白（Aa）肽的产生的发现，我们开始了一系列研究来检查这种跨膜β-淀粉基蛋白酶的功能作用。我们提供的证据支持我们的假设，即BACE 1和BACE 2的分布和水平，沿着APR，是大脑对Aa淀粉样变性选择性易感性的关键决定因素。重要的是，BACE 1的缺失消除了Aa沉积，并防止了突变型APP;PS1小鼠大脑中发生的认知缺陷。虽然BACE 1基因敲除小鼠没有表现出明显的发育异常，但我们最近的研究表明，这些动物在认知和情感测试中的表现确实发生了变化。项目1的目标是评估BACE 1和BACE 2的功能作用，并严格评价BACE 1作为治疗AD的高优先级治疗靶点。因此，目的1中的研究被设计为检查在BACE 1 - 1-、BACE 2 - 1-或BACE 1 - 1-、BACE 2 - 1-小鼠中是否发生突触功能缺陷或认知/行为异常。在目的2，我们计划研究Aa肽异常积累和突触异常发生在APPswe之间的联系;PSl？E9小鼠。这些研究对于目标3至关重要，目标3旨在评估在Aa淀粉样变性和变性的不同阶段BACE 1实验性减少后的可逆性/恢复程度。我们预计，新的机制为基础的治疗，如BACE 1抑制剂将成为在未来可用，因此，重要的是要前瞻性地解决Aa诱导异常的可逆性和大脑的自我修复能力的问题。目的3中的研究旨在确定Aa沉积和相关异常在Aa沉积开始后的不同时间在BACE 1活性降低后可以逆转到何种程度。总之，这些研究的结果将提供有关BACE 1和BACE 2生理作用的重要信息，并允许对BACE 1作为治疗靶点进行关键评价，以减少AD患者的Aa负担。此外，这些研究提供了关于与抗BACE 1治疗相关的潜在机制毒性的重要信息，未来应在临床试验中仔细监测。

项目成果

Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors.

• DOI: 10.1523/jneurosci.1070-10.2010
• 发表时间: 2010-10-13
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wang H;Song L;Lee A;Laird F;Wong PC;Lee HK
• 通讯作者: Lee HK

BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus.

• DOI: 10.1523/jneurosci.2440-08.2008
• 发表时间: 2008-08-27
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Wang H;Song L;Laird F;Wong PC;Lee HK
• 通讯作者: Lee HK