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

描述(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。到目前为止，还没有有效的治疗方法来预防、提示甚至减缓AD的进展，这使得寻找和评估治疗AD的新疗法成为当务之急。鉴于去甲肾上腺素(NA)系统在AD的正常认知功能中起着关键作用，在AD早期就会发生NA神经元的严重丧失，人类患者和动物模型的证据表明NA神经支配的丧失极大地促进了AD的发生和发展，因此，靶向去甲肾上腺素(NA)系统将有利于AD的治疗。然而，靶向NA系统，特别是肾上腺素能受体(ARs)治疗AD的治疗潜力在很大程度上仍未被探索。AR是NA传递的中介体，控制NA输入大脑皮层和该脑区的反应。对AR活性的调控已被证明可以调节神经传递、神经发生和认知行为，从而可能影响AD相关的发病机制和认知功能障碍。本研究的主要目的是通过转基因小鼠模型来确定肾上腺素能药物在延缓AD发病和进展方面的效果。提出了以下两个目标。目的1是确定肾上腺素能操作是否延缓了AD相关病理和认知障碍的发生。在转基因品系中形成淀粉样斑块之前，从3个月大的AD转基因小鼠和非转基因小鼠对照组开始，将用肾上腺素能药物或生理盐水进行治疗。目的2是确定肾上腺素能操作是否延缓了AD相关病理的进展并改善了认知功能。8个月大的小鼠将在转基因品系出现与AD相关的病理和认知障碍后接受治疗。在这两个目标中，与AD相关的病理、神经传递和可塑性以及认知行为将作为结果进行评估。这项研究将为肾上腺素能药物治疗AD的潜在应用提供宝贵的临床前信息，如果成功，将为AD的治疗开辟一个全新的方向。值得注意的是，一些肾上腺素能药物已经在临床上广泛使用。这些药物可以被重新用于治疗AD患者，从而节省了与新药开发相关的时间和成本。 与公共卫生相关：阿尔茨海默病(AD)是毁灭性的老年痴呆的主要原因，目前还没有有效的治疗方法来阻止其发展。本研究阐述了肾上腺素能系统在AD发病机制中的重要性，并探讨了肾上腺素能药物在延缓AD相关病理和认知障碍的发病和进展方面的潜在用途。如果成功，这项研究将为AD的治疗开辟一个全新的方向。值得注意的是，已经在临床上使用的肾上腺素能药物可以被重新用于治疗AD患者，从而节省了与新药开发相关的时间和成本。

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.