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

• 批准号: 8358448
• 负责人: Qin Wang
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358448
• 关键词: APP-PS1; Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Age; Age-Months; Alzheimer' 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

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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the major cause of devastating late-life dementia and currently there are no effective treatments to stop its progression. This study tackles the importance of the adrenergic system in AD pathogenesis, and explores the potential use of adrenergic agents to delay the onset and impede the progression of AD-related pathology and cognitive deficits. If successful, this study would open up an entirely new direction for AD treatment. Significantly, the adrenergic agents which are already used clinically may be repurposed to treat AD patients, thus saving the time and cost associated with new drug development.

描述（由申请人提供）：阿尔茨海默氏病（AD）是毁灭性痴呆症的主要原因。迄今为止，还没有有效的治疗方法可以预防，提示甚至减缓AD的进展，这使得迫切需要识别和评估新颖的AD治疗治疗方法。鉴于NA系统在正常的认知功能中起着至关重要的作用，靶向去甲肾上腺素能（NA）系统对AD的治疗将有益于治疗AD，因此NA神经元在AD的早期发生了严重丧失，并且来自人类患者和动物模型的证据表明，NA神经元的严重丧失表明NA神经元的严重丧失表明NA神经元的严重丧失表明NA神经元的严重丧失表明NA神经元的损失极大地促进了AD病原体和进展。然而，对于AD治疗，通常无法探索NA系统的治疗潜力，尤其是肾上腺素能受体（ARS）。 ARS是NA传播的介体，并控制NA输入到大脑皮质的输入和该大脑区域的结果。 AR活性的操纵已显示出调节神经传递，神经发生和认知行为，因此可能会影响与AD相关的发病机理和认知障碍。这项研究的主要目的是确定肾上腺素能在使用转基因小鼠模型延迟AD的发展和减慢AD进展方面的功效。提出了两个目标，如下所示。目的1是确定肾上腺素能的操纵是否延迟了与广告相关的病理和认知缺陷的发作。 AD转基因小鼠和非转基因同立立物质对照将用肾上腺素能或盐水从3个月大时接受转基因菌株的淀粉样蛋白斑块形成。 AIM 2是确定肾上腺素能的操纵是否会减慢与AD相关的病理的进展并改善认知功能。在转基因菌株中出现了与AD相关的病理和认知缺陷后，将在8个月大时接受小鼠的治疗。在这两个目标中，与广告相关的病理，神经传递和可塑性以及认知行为将被评估为结果。这项研究将提供有关肾上腺素能用来治疗AD的潜在使用的宝贵临床前信息，如果成功，将为AD治疗打开一个全新的方向。值得注意的是，许多肾上腺素能在临床上已经广泛使用。这些药物可以重新使用以治疗AD患者，从而节省与新药开发相关的时间和成本。 公共卫生相关性：阿尔茨海默氏病（AD）是造成毁灭性痴呆症的主要原因，目前尚无有效的治疗方法来阻止其进展。这项研究解决了肾上腺素能系统在AD发病机理中的重要性，并探讨了肾上腺素能剂的潜在用途来延迟发作并阻碍与AD相关的病理学和认知缺陷的进展。如果成功的话，这项研究将为广告处理打开一个全新的方向。值得注意的是，在临床上已经使用的肾上腺素能剂可能会重新使用以治疗AD患者，从而节省了与新药开发相关的时间和成本。