BACE1 in neurodegeneration and neuronal dysfunction

摘要 BACE 1被发现是阿尔茨海默氏病β分泌酶，启动β淀粉样肽（Aβ）的产生。 淀粉样前体蛋白（APP）。Aβ以各种形式（二聚体、三聚体、 多聚体、寡聚体）与阿尔茨海默病（AD）中受损的突触和认知功能有关 患者因此，通过BACE 1抑制减少Aβ生成是一个积极研究的领域， 改善AD患者的认知功能障碍。然而，BACE 1作为一种膜结合型乙酰基蛋白酶， 可以切割APP以外的膜结合蛋白。在其鉴定的底物中，信号分子 神经调节蛋白-1（Nrg 1）和Notch配体如Jagged-1（Jag 1）对于它们在神经系统中的作用是重要的。 发育和突触功能。在本研究中，我们将重点关注BACE 1在信号处理中的作用 例如Nrg 1和Jag 1。在BACE 1基因敲除小鼠中Nrg 1的切割消除减少了Nrg 1 通过ErbB受体的信号传导，从而在发育过程中损害髓鞘形成， 成年人，它也诱导精神分裂症样的行为，包括受损的认知功能。另 另一方面，在BACE 1基因敲除小鼠中，Jag 1的切割消失可能会增加神经元表面的Jag 1信号传导 并以旁分泌方式激活其受体Notch;这种增加的Jag 1-Notch信号传导诱导 在颗粒下区（SGZ）中的星形细胞发生和减少神经发生。SGZ中的神经发生产生 齿状颗粒细胞，其是对长时程增强重要的神经元。因此，需要BACE 1， 正常的神经发育和突触功能。我们的目标是测试我们的中心假设，即BACE 1 信号分子如Nrg 1和Jag 1的切割调节神经发生和突触 功能协调发展的具体来说，我们将1）确定BACE 1依赖性Nrg 1信号转导在控制 突触功能，和2）研究BACE 1依赖性Jag 1信号在星形发生和神经发生。我们 完成这些研究的主要目的是充分了解体内神经元的功能 BACE 1在早期发育和成人大脑中发挥作用，并制定增强 突触功能或神经发生与通过BACE 1降低Aβ的治疗策略相结合 抑制AD患者。

ABSTRACT BACE1 was discovered as the Alzheimer's β-secretase for initiating the production of β-amyloid peptide (Aβ) from amyloid precursor protein (APP). Abnormal accumulation of Aβ in various forms (dimers, trimers, multimers, oligomers) has been linked to impaired synaptic and cognitive functions in Alzheimer's disease (AD) patients. Reducing Aβ generation by BACE1 inhibition is therefore an actively investigated area for ameliorating cognitive dysfunction in AD patients. However, BACE1, as a membrane-bound aspartyl protease, can cleave membrane-bound proteins other than APP. Among its identified substrates, the signaling molecule neuregulin-1 (Nrg1) and Notch ligands such as Jagged-1 (Jag1) are important for their roles in neural development and synaptic functions. In this study, we will focus on the roles of BACE1 in processing signaling molecules such as Nrg1 and Jag1. The abolished cleavage of Nrg1 in BACE1-null mice reduces Nrg1 signaling through ErbB receptors and thus impairs myelination during development and remyelination in the adult, and it also induces schizophrenia-like behaviors, including impaired cognitive functions. On the other hand, abolished cleavage of Jag1 in BACE1-null mice likely increases Jag1 signaling on the neuronal surface and activation of its receptor Notch in a paracrine fashion; this increased Jag1-Notch signaling induces astrogenesis and reduces neurogenesis in the subgranular zone (SGZ). Neurogenesis in the SGZ produces dentate granule cells, which are neurons important for long-term potentiation. Hence, BACE1 is required for normal neural development and synaptic functions. We aim to test our central hypothesis that BACE1 cleavage of signaling molecules such as Nrg1 and Jag1 regulates neurogenesis and synaptic functions. Specifically, we will 1) determine the role of BACE1-dependent Nrg1 signaling in the control of synaptic function, and 2) investigate BACE1-dependent Jag1 signaling in astrogenesis and neurogenesis. Our main objectives for accomplishing the proposed studies are to fully understand the in vivo neuronal functions that BACE1 exerts during early development and in the adult brain and to develop strategies for enhancing synaptic functions or neurogenesis to couple with therapeutic strategies of reducing Aβ through BACE1 inhibition in AD patients.