Mechanisms of acute brain BACE1 regulation

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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.