BACE1 in neurodegeneration and neuronal dysfunction

描述（由申请人提供）：BACE 1是一种I型跨膜β-酰基蛋白酶，其对于在-位点切割淀粉样前体蛋白（APP）是必需的。只有在这种初始切割后，β-分泌酶才进一步加工释放的APP C-末端片段以切除β-淀粉样肽（A）。虽然抑制BACE 1活性将减少BACE 1对APP的加工，从而减少A的释放，但这种抑制也将导致另一种BACE 1底物神经调节蛋白-1（Nrg 1）的切割减少，并将降低其信号传导活性，该活性调节各种中枢神经系统功能，如髓鞘形成、突触可塑性和星形细胞发生。我们已经证明，基因缺失BACE 1导致髓鞘形成不足，可能通过减少Nrg 1信号。BACE 1基因敲除小鼠也表现出精神分裂症样行为、癫痫发作和神经变性，表明BACE 1在许多脑功能中起着关键作用。在这项提议中，我们将专门研究Nrg 1信号传导对观察到的表型的贡献，因为BACE 1基因敲除小鼠中表现出的许多神经功能障碍可能与Nrg 1/ErbB信号通路的改变有关。我们将检验我们的中心假设，即BACE 1依赖性Nrg 1信号传导活性降低导致BACE 1缺失小鼠中观察到的多种神经功能障碍。具体来说，我们将回答重要的问题，即是否提高Nrg 1信号传导活性将改善或加剧BACE 1-null表型通过检查BACE 1-null小鼠基因工程表达BACE 1切割Nrg 1 N-末端片段，以及是否敲入小鼠与破坏切割Nrg 1将产生模拟BACE 1-null小鼠的表型。这项研究的结果不仅将解决许多与BACE 1和Nrg 1功能相关的模糊问题，而且还将为增强Nrg 1信号传导活性是否会逆转或改善与AD患者长期显著抑制BACE 1相关的潜在副作用提供重要指导。 公共卫生相关性：该提案侧重于两种重要分子的研究：BACE 1和神经调节蛋白1（Nrg 1）。BACE 1是产生β-淀粉样肽（A）所需的酶，并且A的过量产生被认为是导致阿尔茨海默病的原因。因此，BACE 1的抑制被积极寻求作为阿尔茨海默病的预防和治疗。BACE 1抑制剂会引起基于机制的副作用也尚未得到系统研究。BACE 1基因敲除小鼠表现出多种神经功能障碍，如髓鞘形成不足、精神分裂症样行为、癫痫发作和神经变性，表明BACE 1在许多脑功能中起关键作用。nrg 1是一种信号分子，调节髓鞘形成、突触可塑性、神经发生和胶质细胞生成等，与精神分裂症的发病机制有关。在BACE 1基因敲除小鼠中，Nrg 1信号传导活性似乎降低，本研究将研究这种降低是否足以引起或促成BACE 1基因敲除小鼠的神经功能障碍。这项研究的结果不仅将解决许多与Nrg 1功能相关的模糊问题，而且还将为增强Nrg 1信号传导活性是否会逆转或改善与AD患者中BACE 1的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.