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Preclinical test for the efficacy of adrenergic agents in treatment of AD

肾上腺素能药物治疗AD疗效的临床前试验

基本信息

批准号：
8517552
负责人：
Qin Wang
金额：
$ 17.35万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517552
关键词：
APP-PS1 Adrenergic Agents Adrenergic Antagonists Adrenergic Receptor Age Age-Months Alzheimer&apos s Disease Amyloid Animal Model Automobile Driving Autoreceptors Behavior Brain Brain region Cells Cerebral cortex Clinical Trials Cognition Cognitive Cognitive deficits Cues Data Dementia Deposition Elderly FDA approved Gender Generations Genetic Human Idazoxan Impaired cognition Learning Mediator of activation protein Mirtazapine Modeling Mus Neuraxis Neurons Norepinephrine Outcome Pathogenesis Pathology Patients Performance Pharmaceutical Preparations Phenotype Physiological Play Preclinical Testing Production Rodent Role Saline Senile Plaques Staging Synaptic Transmission Synaptic plasticity System Testing Therapeutic Time Transgenic Mice Transgenic Model Transgenic Organisms Yohimbine adrenergic aged amyloid pathology base cognitive function cost drug development effective therapy functional outcomes improved morris water maze mouse model nerve supply neurogenesis neurotransmission noradrenergic novel therapeutics postsynaptic pre-clinical preclinical study presynaptic prevent response transgenic model of alzheimer disease transmission process

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the major cause of devastating late-life dementia. To date, there are no effective treatments to prevent, cue or even slow the progression of AD, which makes it urgent to identify and evaluate novel therapeutics for AD treatment. It has been suggested that targeting the noradrenergic (NA) system would be beneficial for treatment of AD, given that the NA system plays a critical role in normal cognitive functions, profound loss of NA neurons occurs at the early stage of AD, and evidence from both human patients and animal models indicates that loss of NA innervation greatly facilitates AD pathogenesis and progression. However, the therapeutic potential of targeting the NA system in general, and the adrenergic receptors (ARs) in particular, for AD treatment remains largely unexplored. ARs are mediators of NA transmission and control both NA input to the cerebral cortex and the resulting response in this brain region. Manipulation of AR activity has been shown to regulate neurotransmission, neurogenesis and cognitive behaviors, and thus might impact AD-related pathogenesis and cognitive impairment. The primary objective of this study is to determine the efficacy of adrenergic agents in delaying the onset and slowing the progression of AD using transgenic mouse models. Two aims are proposed as follows. Aim 1 is to determine if adrenergic manipulation delays the onset of AD-related pathology and cognitive deficits. AD transgenic mice and nontransgenic littermate controls will be treated with adrenergic agents or saline starting at 3 months of age, prior to amyloid plaque formation in the transgenic strains. Aim 2 is to determine if adrenergic manipulation slows the progression of AD-related pathology and improves cognitive function. Mice will be treated at 8 months of age, after AD-related pathology and cognitive deficits have developed in the transgenic strains. In both aims, AD-related pathology, neurotransmission and plasticity, and cognitive behaviors will be evaluated as outcomes. This study will provide invaluable preclinical information on the potential use of adrenergic agents to treat AD, and if successful, would open up an entirely new direction for AD treatment. Significantly, a number of adrenergic agents are already widely used clinically. These drugs may be repurposed to treat AD patients, thus saving time and cost associated with new drug development.

描述（由申请人提供）：阿尔茨海默病（AD）是毁灭性的晚年痴呆症的主要原因。迄今为止，还没有有效的治疗方法来预防、提示甚至减缓AD的进展，这使得迫切需要鉴定和评估用于AD治疗的新疗法。已经提出，靶向去甲肾上腺素能（NA）系统将有益于治疗AD，因为NA系统在正常认知功能中起关键作用，NA神经元的严重损失发生在AD的早期阶段，并且来自人类患者和动物模型的证据表明NA神经支配的损失极大地促进AD的发病机制和进展。然而，靶向NA系统，特别是肾上腺素能受体（AR），用于AD治疗的治疗潜力在很大程度上仍未开发。AR是NA传递的介质，并控制NA输入到大脑皮层和在该脑区域产生的反应。AR活性的调控可以调节神经传递、神经发生和认知行为，从而影响AD相关的发病机制和认知障碍。本研究的主要目的是使用转基因小鼠模型确定肾上腺素能药物在延迟AD发作和减缓AD进展方面的疗效。提出两个目标如下。目的1是确定肾上腺素能操作是否延迟AD相关病理和认知缺陷的发作。AD转基因小鼠和非转基因同窝对照小鼠将在转基因品系中淀粉样蛋白斑块形成之前，从3月龄开始用肾上腺素能药物或生理盐水处理。目的2是确定肾上腺素能操作是否减缓AD相关病理的进展并改善认知功能。在转基因品系中出现AD相关病理学和认知缺陷后，将在8月龄时对小鼠进行治疗。在这两个目标中，AD相关病理学、神经传递和可塑性以及认知行为将作为结局进行评价。这项研究将为肾上腺素能药物治疗AD的潜在用途提供宝贵的临床前信息，如果成功，将为AD治疗开辟一个全新的方向。值得注意的是，许多肾上腺素能药物已经在临床上广泛使用。这些药物可以重新用于治疗AD患者，从而节省与新药开发相关的时间和成本。