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(申请人提供)：阿尔茨海默病(AD)是一种与记忆功能障碍有关的神经退行性疾病。家族性AD患者的病理性突变已在多个基因中被发现，并产生了携带病理性基因的转基因小鼠。淀粉样变性转基因模型的建立极大地促进了旨在降低脑淀粉样β蛋白(Abeta)负荷的治疗方法的发展。其中一种方法被称为“免疫”。免疫激发(或被动注射)的抗Abeta抗体已被证明可以增强小胶质细胞的吞噬功能，并降低转基因小鼠大脑中的Abeta负荷。值得注意的是，免疫还逆转了Abeta相关的记忆功能障碍。伴随着CNS Abeta降低的是，我们和其他人同时观察到，免疫后血浆Abeta水平显著升高。作为这一观察的结果，我们设计了一种新的方法来改变脑Abeta负荷，这在初步研究中被证明是有效的。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部炎症后，终止了Abeta疫苗方案。脑部炎症副作用的原因尚不清楚，但很可能是由于免疫调节。尽管疫苗疗法的第一次临床试验被终止，但后续报告令人鼓舞。隔离方法不调节免疫反应；因此，信息技术治疗在药物开发方面具有较高的灵活性，基于隔离方法的药物副作用较小。此外，当这种方法转化为临床应用时，血浆Abeta升高可能是一个生物标记物。在这项研究中，我们将探讨Abeta的隔离机制，并为未来药物治疗的发展寻找最佳的分子性质和药物靶点。

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