Mechanisms of acute brain BACE1 regulation

被称为β-淀粉样多肽的小肽(氨基酸短链)的积累对神经元网络有害，并导致神经元死亡和功能障碍。导致这些多肽积累的机制是多方面的。我的实验室旨在了解这些大脑β-淀粉样肽是如何产生、积累、清除和降解的。β-位点淀粉样前体蛋白裂解酶1(BACE1)启动淀粉样前体蛋白加工，导致β-淀粉样多肽的产生。然而，调节BACE1在大脑中的表达、活性和周转的亚细胞机制尚不清楚。我们最近报道，一次运动会导致高脂喂养的小鼠BACE1含量和活性下降。在接下来的五年里，我的研究计划将通过急性运动来研究调节BACE1的机械途径。导致BACE1下降的运动诱导信号尚不清楚，但脑内脑源性神经营养因子(BDNF)和白细胞介素6(IL-6)均随运动而增加，可能在调节运动对脑BACE1的影响中发挥重要作用。目前研究的目的是确定BDNF和/或IL-6是否参与调节BACE1的潜在机制。我们认为BDNF和IL-6中的一种或两种都介导了BACE1含量和活性的急性调节。为了在未来五年内研究这一点，我们将：1)确定BNDF和/或IL-6是否直接降低BACE1的含量和活性；2)确定BACE1蛋白含量的减少是否是由于BDNF或IL-6诱导的蛋白酶途径的激活；以及3)确定急性运动降低BACE1含量和活性的效果是否需要BDNF或IL-6。我们将在野生型和转基因小鼠身上使用细胞和组织培养技术的组合，结合体内饮食和运动治疗。这种方法将为我实验室的本科生和研究生提供一个出色的培训环境。我们将确定BDNF和/或IL-6是否是在运动诱导的BACE1含量和活性下降中发挥关键作用的诱导因子。总而言之，这些研究的结果将极大地提高我们对大脑如何对高脂肪喂养和锻炼等生理压力做出反应的过程的基本理解。

The accumulation of small peptides (short chains of amino acids) known as beta-amyloid peptides is detrimental to neuronal networks and leads to neuronal death and dysfunction. The mechanisms leading to the accumulation of these peptides are multifaceted. My lab aims to understand the how these brain beta-amyloid peptides are produced, accumulated, cleared, and degraded. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates amyloid precursor protein processing leading to the production of beta-amyloid peptides. However, the sub-cellular mechanisms that regulate the expression, activity, and turnover of BACE1 in the brain are unknown. We have recently reported that one bout of exercise leads to declines in BACE1 content and activity in high fat fed mice. For the next five years my research program will examine the mechanistic pathways involved in the regulation of BACE1 with acute exercise. The exercise induced signals that lead to this decline in BACE1 are unknown, however brain derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) are both increased in the brain with exercise and may play an important role in modulating the effects of exercise on brain BACE1. The purpose of the current research is to determine if BDNF and or IL-6 are involved in the underlying mechanisms that regulate BACE1. We believe that either one or both BDNF and IL-6 mediate the acute regulation of BACE1 content and activity. To examine this over the next five years we will: 1) determine if BNDF and/or IL-6 directly reduce BACE1 content and activity; 2) determine if reductions in BACE1 protein content are due to BDNF or IL-6 induced activation of protease pathways; and 3) determine if BDNF or IL-6 are required for the effects of acute exercise on reducing BACE1 content and activity. We will use a combination of cell and tissue culture techniques in combination with in vivo diet and exercise treatments in wild type and genetically modified mice. This approach will provide an outstanding training environment for undergraduate and graduate students in my lab. We will determine if BDNF and/or IL-6 are inducible factors that play a pivotal role in the exercise-induced reduction in BACE1 content and activity. Together the results of these investigations will greatly increase our fundamental understanding of the processes that underlie how the brain responds to physiological stressors such as high fat feeding and exercise.