Natural Product Therapeutics in Alzheimer's Disease

阿尔茨海默病的天然产物疗法

• 批准号: 7088800
• 负责人: TAE-WAN KIM
• 金额: $ 47.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-29 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088800
• 关键词: Alzheimer' s disease; alternative medicine; amyloid proteins; behavior test; biological products; biotechnology; brain disorder chemotherapy; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; electrophysiology; enzyme linked immunosorbent assay; functional magnetic resonance imaging; genetically modified animals; image processing; inhibitor /antagonist; laboratory mouse; nonhuman therapy evaluation; pathologic process; pharmacokinetics; plant extracts; polymerase chain reaction

DESCRIPTION (PROVIDED BY APPLICANT): Genetic, biochemical and neuropathological studies support the idea that cerebral elevation and accumulation of the amyloid beta-peptide (Ab) are early and necessary steps in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by sequential proteolytic cleavages of the amyloid precursor protein (APP) by a set of membrane-bound proteases termed beta-and gamma-secretases. Heterogeneous gamma-secretase cleavage at the C-terminal end of Abeta produces two major isoforms of Abeta, Abeta40 and Abeta42. While Abeta40 is the predominant cleavage product, the less abundant, highly amyloidogenic Abeta42 is believed to be one of the key pathogenic agents in AD and increased cerebrocorical Abeta42 is closely related to synaptic/neuronal dysfunction associated with AD. Furthermore, mutations in the APP and presenilin genes that cause rare early-onset forms of familial Alzheimer's disease (FAD), universally lead to an increased production of Abeta42. Thus, agents which are able to selectively reduce Abeta42 production are attractive and promising as therapeutic reagents for treating AD. Our preliminary studies showed that several triterpene natural products (known as "ginsenosides") derived from heat-processed ginseng (e.g. red ginseng), selectively lower the production of Abeta42. Based on this key preliminary data, the major goal of this proposal is to investigate the mechanistic basis of anti-amyloid (e.g. Abeta42-reducing) activity of these ginsenosides and other related natural products, and to evaluate their therapeutic potential using in vitro and in vivo models of (AD). To address these issues, we will carry out the following Specific Aims: (1) To investigate the mechanism of the anti-amyloid activity of selected ginsenosides; (2) To investigate the effects of Abeta42-lowering ginsenosides on Alzheimer-like pathology in a mouse model of AD; (3) To test the effects of Abeta42-lowering ginsenosides on neuronal dysfunction in a mouse model of AD: parallel analyses using fMRI, electrophysiology and behavioral approaches. Since these Abeta42-reducing ginsenosides can directly antagonize the key pathological event in AD, successful completion of our studies will help determine the therapeutic benefit of ginsenosides in AD.

描述（由申请人提供）：遗传、生化和神经病理学研究支持这样的观点，即大脑中淀粉样β-肽（Ab）的升高和积累是阿尔茨海默病（AD）发病机制中的早期和必要步骤。 Abeta 是通过一组称为 β 和 γ 分泌酶的膜结合蛋白酶对淀粉样前体蛋白 (APP) 进行连续蛋白水解裂解而产生的。 Abeta C 末端的异源 γ-分泌酶裂解产生 Abeta 的两种主要亚型：Abeta40 和 Abeta42。虽然 Abeta40 是主要的裂解产物，但含量较低、高度淀粉样蛋白生成的 Abeta42 被认为是 AD 的关键致病因子之一，并且脑皮质 Abeta42 的增加与 AD 相关的突触/神经元功能障碍密切相关。此外，导致罕见的早发性家族性阿尔茨海默病 (FAD) 的 APP 和早老素基因突变通常会导致 Abeta42 的产生增加。因此，能够选择性减少Abeta42产生的试剂作为治疗AD的治疗试剂是有吸引力且有前景的。我们的初步研究表明，从热加工人参（例如红参）中提取的几种三萜天然产物（称为“人参皂苷”）可选择性降低 Abeta42 的产生。基于这些关键的初步数据，该提案的主要目标是研究这些人参皂苷和其他相关天然产物的抗淀粉样蛋白（例如 Abeta42 减少）活性的机制基础，并利用体外和体内评估其治疗潜力。 (AD)的体内模型。针对这些问题，我们将开展以下具体目标：（1）研究选定人参皂苷的抗淀粉样蛋白活性机制； (2) 研究降低 Abeta42 的人参皂苷对 AD 小鼠模型中阿尔茨海默样病理的影响； (3) 测试降低 Abeta42 的人参皂苷对 AD 小鼠模型神经元功能障碍的影响：使用功能磁共振成像、电生理学和行为方法进行平行分析。由于这些减少 Abeta42 的人参皂苷可以直接拮抗 AD 中的关键病理事件，因此我们研究的成功完成将有助于确定人参皂苷在 AD 中的治疗益处。