Mechanism of Abeta Sequestration

Abeta 封存机制

• 批准号: 8020909
• 负责人: RAYMOND SCOTT TURNER
• 金额: $ 26.7万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020909
• 关键词: Active Immunization; Adverse effects; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; Amyloidosis; Antibodies; Binding; Biological Markers; Brain; Clinical; Clinical Trials; Development; Disease; Encephalitis; Functional disorder; Future; Generations; Genes; Human; Immune; Immunization; Inflammatory; Memory; Methodology; Molecular; Mutation; Nerve Degeneration; Patients; Phagocytosis; Pharmaceutical Preparations; Plasma; Property; Reaction; Reporting; Research Proposals; Site; Therapeutic; Therapeutic Agents; Transgenic Mice; Transgenic Model; Translating; Vaccine Therapy; Vaccines; base; design; drug development; familial Alzheimer disease; flexibility; follow-up; immunoregulation; therapeutic development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Pathological mutations in familial AD patients have been identified in several genes, and transgenic mice carrying pathological genes have been generated. The generation of transgenic models of amyloidosis has significantly aided progress in the development of therapeutic approaches designed to lower brain amyloid beta (Abeta) load. One of these approaches is called "immunization". Immunologically provoked (or passively administered) antibodies against Abeta have been shown to enhance microglial phagocytosis and reduce Abeta load in the brains of transgenic mice. Significantly, immunization also reversed Abeta associated memory dysfunction. Concomitant with reduced CNS Abeta is the simultaneous observation by us and others that plasma Abeta levels are significantly elevated following immunization. As a result of this observation, we have devised a new methodology to alter brain Abeta load, which has proved to be effective in preliminary studies. In the human active immunization clinical trial, Abeta vaccine approach was terminated after severe brain inflammation was found approximately in 6% of patients. The cause of brain inflammatory side effects is not clear yet, but it is most likely due to immune modulation. Although the first clinical trial of vaccine therapy was terminated, follow up reports are encouraging. Sequestration approach does not modulate immune reaction; therefore, it therapy has higher flexibility in drug development, and drugs based on sequestration approaches have less side effects. In addition, plasma Abeta elevation is a possible biomarker when this approach translates to clinical use. In this study, we will investigate the mechanism of Abeta sequestration mechanism and identify optimal molecular property and drugable target for future development of pharmacological therapy.

描述（由申请人提供）：阿尔茨海默病（AD）是一种与记忆功能障碍相关的神经退行性疾病。家族性AD患者的病理性突变已经在几个基因中被鉴定，并且已经产生了携带病理性基因的转基因小鼠。淀粉样变性的转基因模型的产生显著地帮助了旨在降低脑淀粉样蛋白β（Abeta）负荷的治疗方法的发展。这些方法之一被称为“免疫”。免疫激发的（或被动施用的）抗Abeta抗体已显示增强转基因小鼠脑中小胶质细胞的吞噬作用并降低Abeta负荷。值得注意的是，免疫也逆转了Abeta相关的记忆功能障碍。与CNS Abeta降低相伴随的是我们和其他人同时观察到免疫后血浆Abeta水平显著升高。由于这一观察结果，我们设计了一种新的方法来改变大脑Abeta负荷，这在初步研究中已被证明是有效的。在人类主动免疫临床试验中，在大约6%的患者中发现严重的脑炎症后，Abeta疫苗方法被终止。大脑炎症副作用的原因尚不清楚，但最有可能是由于免疫调节。虽然第一次疫苗治疗的临床试验已经终止，但后续报告令人鼓舞。隔离方法不调节免疫反应，因此，它在药物开发中具有更高的灵活性，并且基于隔离方法的药物具有更小的副作用。此外，当这种方法转化为临床应用时，血浆Abeta升高是一种可能的生物标志物。在本研究中，我们将探讨Abeta螯合机制，并确定最佳的分子特性和药物靶点，为未来的药物治疗发展。

项目成果

Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease.

• DOI: 10.1016/j.expneurol.2012.10.005
• 发表时间: 2013-01
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Sung, You Me;Lee, Taehee;Yoon, Hyejin;DiBattista, Amanda Marie;Song, Jung Min;Sohn, Yoojin;Moffat, Emily Isabella;Turner, R. Scott;Jung, Mira;Kim, Jungsu;Hoe, Hyang-Sook
• 通讯作者: Hoe, Hyang-Sook

Decreased dendritic spine density and abnormal spine morphology in Fyn knockout mice.

• DOI: 10.1016/j.brainres.2011.07.059
• 发表时间: 2011-09-30
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Babus LW;Little EM;Keenoy KE;Minami SS;Chen E;Song JM;Caviness J;Koo SY;Pak DT;Rebeck GW;Turner RS;Hoe HS
• 通讯作者: Hoe HS

Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease.

• DOI: 10.1111/jnc.12059
• 发表时间: 2013-01
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Choi SH;Aid S;Caracciolo L;Minami SS;Niikura T;Matsuoka Y;Turner RS;Mattson MP;Bosetti F
• 通讯作者: Bosetti F

ApoE receptor 2 regulates synapse and dendritic spine formation.

• DOI: 10.1371/journal.pone.0017203
• 发表时间: 2011-02-15
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dumanis SB;Cha HJ;Song JM;Trotter JH;Spitzer M;Lee JY;Weeber EJ;Turner RS;Pak DT;Rebeck GW;Hoe HS
• 通讯作者: Hoe HS