Understanding the Neuroprotective Activities of Posiphen

了解 Posiphen 的神经保护活性

• 批准号: 8692627
• 负责人: KUMAR SAMBAMURTI
• 金额: $ 18.69万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692627
• 关键词: 5' Untranslated Regions; A Mouse; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Amyloidosis; Animal Model; Animals; Behavior; Bioavailable; Biological Markers; Biological Preservation; Brain; Canis familiaris; Cell Culture Techniques; Cholinesterases; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Clinical; Clinical Drug Development; Cognition; Dementia; Deposition; Deterioration; Dose; Down Syndrome; Drug Design; Drug Targeting; Event; Exhibits; Failure; Future; Genetic Translation; Goals; Homeostasis; Human; Human Chromosomes; Hyperhomocysteinemia; Immunotherapy; Impaired cognition; Impairment; Individual; Institutes; Intervention; Lesion; Life; Measures; Mediating; Metabolic Pathway; Methods; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Oral Administration; Pathogenesis; Pathology; Patients; Phase I Clinical Trials; Phenotype; Plasma; Presenile Alzheimer Dementia; Property; Protein Biosynthesis; Proteins; Reducing Agents; Risk Factors; Rodent; Role; Senile Plaques; Tartrates; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Translations; Weaning; amyloid pathology; basal forebrain cholinergic neurons; cholinergic; familial Alzheimer disease; gamma secretase; grasp; hypercholesterolemia; improved; mouse Ts65Dn; mouse model; neuron loss; neuropathology; neuroprotection; novel; phenserine; presenilin; prevent; protein expression; public health relevance; secretase; small molecule; tau Proteins; theories; tool

DESCRIPTION (provided by applicant): Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology early in life, and develop progressive cognitive impairment in their fourth or fifth decade. Transgenic mice expressing Amyloid beta protein (A¿) precursor (APP) deposit amyloid but do not present degeneration phenotypes. A mouse model of DS, the Ts65Dn mice, suffers degeneration of a number of neuronal subtypes, including the basal forebrain cholinergic neurons that are lost in AD. This appears to require APP duplication although high APP is not sufficient to induce neurodegeneration in transgenic mice. We previously identified a novel compound - Posiphen - that inhibits APP translation by regulating the 5'-untranslated region of APP. We are planning to reduce APP expression by treating animal models with Posiphen to determine whether long-term treatment could arrent AD like pathology and if neurodegeneration in DS can be prevented by this treatment. The neurodegeneration in the TS65Dn mice appears to depend on APP making it a useful model to evaluate neuroprotection by anti-APP therapies. This R21 project will test the hypothesis that reduction of APP synthesis will restore homeostasis of this highly expressed protein and therefore prevent neuronal loss and behavior in DS mice. The second hypothesis is that Posiphen treatment will reduce amyloid accumulation as plaques. In future studies, we plan to continue collaborating with Dr. Nigel Greig for clinical development of the drug. The two specific aims of the project are: 1) Evaluate the effects of Posiphen treatment in the TS65Dn mice, which naturally express 1.5 times higher levels of APP and accumulate secreted APP derivatives with age; 2) Determine the effect of Posiphen on amyloid deposition in transgenic mouse models. We hypothesize that the treatment will successfully reduce neurodegeneration in the DS mouse model and provide us with the tools to identify the late and windows that may be targeted for intervention.

描述（由申请人提供）：唐氏综合征（DS）患者在生命早期表现出阿尔茨海默病（AD）神经病理学，并在40或50岁时发展为进行性认知障碍。表达淀粉样β蛋白（A？）前体（APP）的转基因小鼠存款淀粉样蛋白，但不呈现变性表型。DS的小鼠模型Ts 65 Dn小鼠遭受许多神经元亚型的变性，包括在AD中丢失的基底前脑胆碱能神经元。这似乎需要APP复制，尽管高APP不足以诱导转基因小鼠的神经变性。我们以前发现了一种新的化合物- Posiphen -通过调节APP的5 '-非翻译区来抑制APP的翻译。我们计划通过用Posiphen治疗动物模型来减少APP的表达，以确定长期治疗是否可以防止AD样病理，以及这种治疗是否可以预防DS中的神经变性。TS 65 Dn小鼠中的神经变性似乎依赖于APP，使其成为评估抗APP疗法的神经保护作用的有用模型。该R21项目将测试这样的假设，即APP合成的减少将恢复这种高度表达的蛋白质的稳态，从而防止DS小鼠的神经元损失和行为。第二个假设是Posiphen治疗将减少淀粉样蛋白作为斑块的积累。在未来的研究中，我们计划继续与奈杰尔格雷格博士合作进行药物的临床开发。该项目的两个具体目标是：1）评估Posiphen治疗TS 65 Dn小鼠的效果，这些小鼠天然表达1.5倍高水平的APP，并随着年龄的增长积累分泌的APP衍生物; 2）确定Posiphen对转基因小鼠模型中淀粉样蛋白沉积的影响。我们假设该治疗将成功减少DS小鼠模型中的神经退行性变，并为我们提供工具来识别可能用于干预的晚期和窗口。