BACE1 in neurodegeneration and neuronal dysfunction

描述（由申请人提供）：BACE1是一种I型跨膜天冬氨酸蛋白酶，对在-位点切割淀粉样前体蛋白（APP）至关重要。只有在初始裂解后-分泌酶才会进一步处理释放的APP c端片段以去除-淀粉样肽(A)。抑制BACE1活性会减少APP的BACE1加工，从而减少A的释放，同时这种抑制也会导致另一种BACE1底物神经调节蛋白-1 （neuroregulin -1, Nrg1）的切割减少，并降低其信号转导活性，从而调节多种中枢神经系统功能，如髓鞘形成、突触可塑性和星形胶质发生。我们已经证明，基因缺失BACE1可能通过减少Nrg1信号传导导致髓鞘退化。BACE1缺失的小鼠也表现出精神分裂症样行为、癫痫发作和神经变性，这表明BACE1在许多脑功能中起着关键作用。在本提案中，我们将专门研究Nrg1信号对观察到的表型的贡献，因为在bace1缺失的小鼠中表现出的许多神经功能障碍可能与Nrg1/ErbB信号通路的改变有关。我们将验证我们的中心假设，即bace1依赖性Nrg1信号活性降低有助于观察到bace1缺失小鼠的多种神经功能障碍。具体来说，我们将通过检测表达bace1切割的Nrg1 n端片段的bace1缺失小鼠，以及Nrg1切割被破坏的敲入小鼠是否会产生模仿bace1缺失小鼠的表型，来回答Nrg1信号活性升高是否会改善或加剧bace1缺失表型的重要问题。本研究的结果不仅将解决许多与BACE1和Nrg1功能相关的模糊问题，而且还将为增强Nrg1信号活性是否会逆转或改善AD患者中长期显著抑制BACE1相关的潜在副作用提供重要指导。

DESCRIPTION (provided by applicant): BACE1 is a type I transmembrane aspartyl protease which is essential for cleaving amyloid precursor protein (APP) at the -site. Only after this initial cleavage does - secretase further process the released APP C-terminal fragment to excise -amyloid peptide (A). While inhibiting BACE1 activity will reduce BACE1 processing of APP and will thus reduce the release of A, this inhibition will also lead to decrease cleavage of another BACE1 substrate, neuregulin-1 (Nrg1), and will reduce its signaling activity, which regulates various central nervous system functions such as myelination, synaptic plasticity and astrogenesis. We have demonstrated that genetic deletion of BACE1 causes hypomyelination, perhaps via reduced Nrg1 signaling. BACE1-null mice also exhibit schizophrenia-like behaviors, epileptic seizures and neurodegeneration, indicating that BACE1 plays a critical role in many brain functions. In this proposal, we will specifically investigate the contribution of Nrg1 signaling to the observed phenotypes because many of these neurological dysfunctions exhibited in BACE1-null mice are potentially related to alterations in the Nrg1/ErbB signaling pathway. We will test our central hypothesis that reduced BACE1-dependent Nrg1 signaling activity contributes to the observed multiple neurological dysfunctions in BACE1-null mice. Specifically, we will answer important questions as to whether elevated Nrg1 signaling activity will ameliorate or exacerbate BACE1-null phenotypes through examining BACE1-null mice engineered to express BACE1-cleaved Nrg1 N-terminal fragment and whether knock-in mice with disrupted cleavage in Nrg1 will produce phenotypes mimicking BACE1-null mice. Results from this study will not only resolve many ambiguous questions related to BACE1 and Nrg1 functions, but will also provide important guidance as to whether enhancing Nrg1 signaling activity will reverse or ameliorate potential side effects associated with long-term significant inhibition of BACE1 in AD patients.