Neural Aging and A Toxicity Assessments, a Fly Pharmacology-Molecular AD Model

苍蝇药理学-分子阿尔茨海默病模型的神经老化和抗体毒性评价 摘要： 人类研究表明，蛋白质聚集体(Aβ42)的逐渐积累是 神经退行性疾病的发展，包括阿尔茨海默病(AD)。因此，一个重要的 自那以后，AD研究的一部分集中在Aβ42在维持中的来源和细胞毒性作用， 应激反应和神经元功能衰退。然而，老年科学研究强调了其他 代谢、蛋白分解、应激反应和细胞信号通路也与衰老和 神经退行性变过程。现已发现，AD的危险因素包括先天性免疫的慢性激活 (发炎)和蛋白分解清除受损。此外，与AD相关的进程，如NFkb信令 APP的处理也与神经发育和突触重塑有关。这表明一个 更少的关注，更微妙的老年科学方法来研究AD和潜在的治疗方法是必要的。我们的工作 关于老年学的研究主要集中在利用衰老的果蝇模型进行自噬的作用。我们发现 神经元的自噬能力与聚集体的形成、应激反应和 果蝇的寿命概况。使用苍蝇衰老模型，我们已经确定了饮食(间歇禁食，如果)和 促进自噬和神经元功能的药物治疗方案。这在一定程度上是通过恢复更年轻的状态 老年神经组织中的基因表达和转录漂移变异(TDV)谱。具有特殊的机械性 重要的是与年龄有关的蛋白质分解成分的严重失调，这在很大程度上是 被If抑制。我们建立了第二个果蝇模型，检测创伤性脑损伤(TBI)。vbl.使用 在标准化条件下，经脑创伤处理的果蝇表现出保守的途径变化(自噬，NFkb)，行为 已知的人类创伤患者和啮齿动物的缺陷(运动、睡眠)和分子改变 模特们。我们发现，衰老和成年果蝇的遗传背景改变了脑损伤的反应，选择药物也是如此 (J147)或如果接受治疗。这个应用程序的目标是使用AD果蝇采取一种集成的方法 研究体内聚集体形成(Aβ42-北极)对老化或受损的中枢神经系统的影响的模型。 这一提议的中心假设是，共同的保护性分子通路可以通过 动物模型和这些独特的机制洞察力可以被用来开发新的治疗方法 用于复杂的衰老和神经退行性疾病。特定目标1将确定组织特定的影响 β42北极的产生对成人神经老化、脑外伤依赖表型和寿命曲线的影响 果蝇。在具体目标2中，我们将使用我们的果蝇神经老化、创伤和AD模型来确定 精选日粮(IF)和化合物(J147)延缓或抑制许多相关表型的有效性 神经退行性疾病。这一建议的发现将成为未来老年科学研究的基础。 研究神经老化的保守机制和神经保护治疗的识别。

Neural Aging and Ab Toxicity Assessments, a Fly Pharmacology-Molecular AD Model Abstract: Human studies have shown that the progressive accumulation of protein aggregates (Aβ42) is key a factor in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). As a result, a significant portion of AD research has since focused on the origin and cytotoxic effects that Aβ42 has on the maintenance, stress responses and functional decline of neurons. However, geroscience studies have highlighted other metabolic, proteolytic, stress response and cell signaling pathways are also closely linked to aging and neurodegenerative processes. It has emerged that AD risk factors include chronic activation of innate immunity (inflammaging) and impaired proteolytic clearance. In addition, AD associated processes like NFkb signaling and APP processing are also involved with neural development and synaptic remodeling. This indicates that a less focus more nuanced geroscience based approach to study AD and potential therapies is required. Our work on gerontology has largely focused on the role of autophagy using an aging Drosophila model. We found that the autophagic capacity of neurons is directly correlated with aggregate formation, stress responses and longevity profiles of Drosophila. Using a fly aging model, we have identified dietary (intermittent fasting, IF) and drug treatment regimens that promote autophagic and neuronal function. This is in part by restoring more youthful gene expression and transcriptional drift variance (TDV) profiles in aged neural tissues. Of particular mechanistic importance was the profound age-related dysregulation of proteolytic components, which was largely suppressed by IF. We developed a second Drosophila model, examining traumatic brain injury (TBI). Using standardized conditions, TBI-treated flies showed conserved pathway changes (autophagy, NFkb), behavioral defects (locomotion, sleep) and molecular alterations known to occur in human trauma patients and in rodent models. We find that aging and the genetic background of adult flies alters TBI responses, as does select drug (J147) or IF treatment. The goal of this application is to take an integrated approach using an AD Drosophila model to examine the impact that in vivo aggregate formation (Aβ42-Arctic) has on the aging or traumatized CNS. The central hypothesis of this proposal is that common protective molecular pathways can be identified using animal models and these unique mechanistic insights can be exploited to develop new therapeutic treatments for complex aging and neurodegenerative disorders. Specific Aim 1 will determine the impact that tissue specific production of Aβ42-Arctic has on the neural aging and TBI dependent phenotypes and longevity profiles of adult Drosophila. In Specific Aim 2, we will use our Drosophila neural aging, trauma and AD models to determine the effectiveness of select diets (IF) and compounds (J147) to delay or suppress phenotypes associated many neural degenerative disorders. Findings from this proposal will be the foundation for future gerosciene studies examining the conserved mechanisms of neural aging and the identification of neuroprotective treatments.