BACE1 in neurodegeneration and neuronal dysfunction

描述(申请人提供)：BACE1是一种I型跨膜天冬氨酸蛋白酶，对切割淀粉样前体蛋白(APP)是必需的。只有在这种最初的切割之后，分泌酶才会进一步处理释放的APP C末端片段，以切除淀粉样肽(A)。虽然抑制BACE1活性会减少BACE1对APP的加工，从而减少A的释放，但这种抑制也会导致另一种BACE1底物--神经调节蛋白-1(Nrg1)的切割减少，并降低其信号活性，从而调节中枢神经系统的各种功能，如髓鞘形成、突触可塑性和星形胶质形成。我们已经证明，BACE1的基因缺失可能通过Nrg1信号的减少而导致髓鞘减少。BACE1基因缺失的小鼠还表现出精神分裂症样行为、癫痫发作和神经变性，这表明BACE1在许多大脑功能中发挥着关键作用。在这个方案中，我们将专门研究Nrg1信号对观察到的表型的贡献，因为在BACE1基因缺失的小鼠中表现出的许多神经功能障碍可能与Nrg1/ErbB信号通路的变化有关。我们将验证我们的中心假设，即BACE1依赖的Nrg1信号活性减少有助于观察到BACE1缺失小鼠的多种神经功能障碍。具体地说，我们将通过检测BACE1缺失的小鼠来回答重要的问题，即升高的Nrg1信号活性是否会改善或加剧BACE1缺失的表型，以及Nrg1切割中断的敲入小鼠是否会产生类似BACE1缺失小鼠的表型。这项研究的结果不仅将解决许多与BACE1和Nrg1功能相关的模棱两可的问题，而且还将为增强Nrg1信号活性是否逆转或改善AD患者长期显著抑制BACE1的潜在副作用提供重要指导。 与公共卫生相关：该提案侧重于两个重要分子的研究：BACE1和NeuRegin 1(Nrg1)。BACE1是一种产生淀粉样多肽(A)所需的酶，A的过度产生被认为是导致阿尔茨海默病的原因。因此，抑制BACE1被积极应用于阿尔茨海默病的预防和治疗。BACE1抑制剂是否会引起机制上的副作用也尚未有系统的研究。BACE1基因缺失的小鼠表现出多种神经功能障碍，如髓鞘减少、精神分裂症样行为、癫痫发作和神经变性，表明BACE1在许多脑功能中起着关键作用。NRG1是一种信号分子，调节髓鞘形成、突触可塑性、神经发生和胶质形成等，与精神分裂症的发病机制有关。在BACE1基因缺失的小鼠中，Nrg1信号活性似乎降低，这种减少是否足以导致或促成BACE1基因缺失小鼠的神经功能障碍，本研究将对此进行研究。这项研究的结果不仅将解决许多与Nrg1功能相关的模糊问题，而且还将为增强Nrg1信号活性是否逆转或改善与AD患者BACE1长期显著抑制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. PUBLIC HEALTH RELEVANCE: This proposal focuses on the study of two important molecules: BACE1 and neuregulin 1 (Nrg1). BACE1 is an enzyme required for generating -amyloid peptides (A), and excessive production of A is considered to cause Alzheimer's disease. Hence, inhibition of BACE1 is actively pursued as Alzheimer's prevention and therapy. BACE1 inhibitors will cause mechanism-based side effects has also not been systematically investigated. BACE1-null mice exhibit multiple neurological dysfunctions such as hypomyelination, schizophrenia-like behaviors, epileptic seizures and neurodegeneration, indicating that BACE1 plays a critical role in many brain functions. Nrg1 is a signaling molecule that regulates myelination, synaptic plasticity, neurogenesis and gliogenesis, etc., and is linked to the pathogenesis of schizophrenia. In BACE1-null mice, Nrg1 signaling activity appears reduced, and whether this reduction would be sufficient to cause or contribute to the neurological dysfunctions in BACE1-null mice will be investigated in this study. Results from this study will not only resolve many ambiguous questions related to Nrg1 function, but will also provide important guidance as whether enhancing Nrg1 signaling activity will reverse or ameliorate potential side effects associated with the long-lasting significant inhibition of BACE1 in AD patients.