Understanding the Neuroprotective Activities of Posiphen

了解 Posiphen 的神经保护活性

基本信息

批准号：
8573968
负责人：
KUMAR SAMBAMURTI
金额：
$ 22.43万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8573968
关键词：
5&apos Untranslated Regions A Mouse Age Age-Months Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid 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 Protein Precursors 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

项目摘要

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（由适用提供）：唐氏综合症（DS）的患者在生命的早期暴露于阿尔茨海默氏病（AD）神经病理学，并在其第四或第五个十年中发展出了渐进的认知障碍。表达淀粉样蛋白β蛋白（A a）前体（APP）沉积淀粉样蛋白但不存在变性表型的转基因小鼠。 TS，TS65DN小鼠的小鼠模型遭受了许多神经元亚型的变性，包括AD中丢失的基本前脑胆碱能神经元。尽管高应用不足以诱导转基因小鼠的神经退行性，但这似乎需要应用程序重复。我们先前鉴定出一种新型化合物 - posipher-，该化合物通过计算APP的5'-非翻译区域来抑制应用程序翻译。我们计划通过使用Posipher处理动物模型来降低APP表达，以确定长期治疗是否可以像病理一样到达AD，并且该治疗方法是否可以预防DS中的神经退行性。 TS65DN小鼠中的神经变性似乎取决于应用，使其成为通过抗应用疗法评估神经保护的有用模型。这个R21项目将检验以下假设：APP合成的减少将恢复这种高度表达的蛋白质的稳态，因此可以防止DS小鼠的神经元丧失和行为。第二个假设是，Posipher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Nigel Greig博士合作进行该药物的临床开发。该项目的两个具体目的是：1）评估posipher治疗在TS65DN小鼠中的影响，它们自然地表达了APP的高度1.5倍，并随着年龄的增长而累积分泌的应用程序衍生物； 2）确定Posipher对转基因小鼠模型中淀粉样蛋白沉积的影响。我们假设治疗将成功减少DS小鼠模型中的神经变性，并为我们提供识别可能针对干预的晚期和窗户的工具。