Grape Seed-Derived Polyp: AB Oligom & Spatial in Trans Mice of Alz Dis/Pasinetti

葡萄籽息肉：AB Oligom

• 批准号: 7677434
• 负责人: Giulio Maria Pasinetti
• 金额: $ 41.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7677434
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Attenuated; Brain; Clinical Trials; Cognitive; Data; Dementia; Deposition; Deterioration; Drug Kinetics; Event; Future; Goals; Grapes; In Vitro; Label; Memory impairment; Molecular Weight; Mus; Peptides; Plasma; Polyps; Prevention; Risk; Role; Techniques; Tg2576; accelerator mass spectrometry; attenuation; base; design; extracellular; grape seed; grape seed extract; in vivo; mild neurocognitive impairment; mouse model; neuropathology; neurotoxic; pre-clinical; prevent

A major hallmark of Alzheimer's disease (AD) is the accumulation of neurotoxic p-amyloid (A(3) peptide in the brain. Inappropriate oligomerization of Ap peptides into soluble high molecular weight (HMW) species and the eventual deposition of A(3 peptides into extracellular A(3 plaques in the brain are major events involved in AD neuropathology and associated dementia. Accumulating evidence indicates a central role for soluble A|3 oligomers (with molecular weight higher than tetramers but lower than decamers) in preclinical AD cognitive deterioration as well as in AD dementia. The overall goal of the proposed studies in Project 3 is to identify bioactive grape seed extract (GSE)- polyphenolic compounds that can prevent AD-type amyloid neuropathology and cognitive deterioration in the Tg2576 mouse model of AD. The proposed studies are supported by preliminary evidence showing that a commercially available GSE (herein defined as NS-MA2 GSE) containing a variety of polyphenolic compounds, prevents the oligomerization of Ap peptides into soluble-extracellular HMW species and eventually AD - type Ap neuropathology, coincidental with the attenuation of spatial reference memory impairment in Tg2576 mice. Based on this consideration, the proposed studies are specifically designed to further identify and document how NS-MA2 GSE polyphenolic compounds are absorbed, metabolized and ultimately prevent AD-type cognitive deterioration in Tg2576 mice. The proposed studies will be the first to systematically identify GSE polyphenolic compounds in vivo using a combination of LC-tandem mass spectrorhetry and NMR techniques. Furthermore, this approach will make use of 14C labeled grape fractions and Accelerator Mass Spectrometry to accurately determine the pharmacokinetics of NS-MA2 GSE polyphenolic compounds in plasma and in the brain. Data from the proposed studies will provide impetus for immediate application to prevention of cognitive deterioration in AD, and potentially also in mild cognitive impairment (MCI), whose subjects are at high risk of developing AD dementia.

阿尔茨海默氏病（AD）的主要标志是神经毒性P-淀粉样蛋白的积累（A（3）肽 脑。 AP肽不适当地促成可溶性高分子量（HMW）物种和 A（3个肽中的3个肽在细胞外A（大脑中的3个斑块是参与的主要事件） AD神经病理学和相关痴呆症。积累的证据表明可溶性A | 3的核心作用 临床前AD认知中的低聚物（分子量高于四聚体但低于Decamers） 恶化以及AD痴呆症。项目3中拟议研究的总体目标是确定 生物活性葡萄种子提取物（GSE） - 可以预防AD型淀粉样蛋白的多酚化合物 TG2576 AD小鼠模型中的神经病理学和认知恶化。拟议的研究是 在初步证据的支持下，表明商业上可用的GSE（本文定义为NS-MA2 GSE）包含多种多酚化合物，可防止AP肽的寡聚化 可溶性细胞HMW物种，最​​终AD -type AP神经病理学，与 TG2576小鼠中空间参考记忆障碍的衰减。基于此考虑， 拟议的研究专门设计，以进一步识别和记录NS-MA2 GSE多酚 化合物被吸收，代谢并最终防止TG2576中的AD型认知恶化 老鼠。拟议的研究将是第一个系统地识别体内GSE多酚化合物的研究 结合LC-Tandem质谱和NMR技术的组合。此外，这种方法将 利用14C标记的葡萄级分和加速器质谱法来准确确定 血浆和大脑中NS-MA2 GSE多酚化合物的药代动力学。来自 拟议的研究将为预防认知恶化的立即应用提供动力 AD，也有可能处于轻度认知障碍（MCI），其受试者有发展AD的高风险 失智。