Biochemical and molecular biological mechanisms underlying a to b cleavage and Ab biogenesis in Alzheimer disease

阿尔茨海默病（Alzheimer's disease，AD）是最常见但复杂的异质性遗传性痴呆。患有复杂和异质性AD疾病的脑神经病理学表现出相当同质的特征。这一不可避免的事实简单地表明，淀粉样蛋白β（Aβ）的积累和聚集是AD的主要原因。Aβ是由APP经两次连续裂解而形成的一个约40个氨基酸残基的多肽，参与的蛋白酶有β-分泌酶（一种新型的β-酰基蛋白酶）、β-位点APP裂解酶（β-site APP cleaving enzyme，BACE）和γ-分泌酶（一种含有早老素的多聚体复合物）。在AD患者的脑中，Aβ的产生和降解/清除之间的平衡可能会改变，这是相当合理的。Aβ是由淀粉样前体蛋白（APP）经两次连续裂解而形成的一种约40个氨基酸残基的肽。近年来，我们建立了一个良好的实验性培养心肌细胞系统，在氯喹（chloroquine，CQN）存在或不存在的情况下，研究APP加工产生Aβ的过程。在本实验中，我们检查了Aβ的产生和降解/清除之间的平衡。结果表明，CQN处理后BACE mRNA表达上调，Aβ含量增加，BACE反义寡核苷酸处理后C99、β-分泌酶切割的C端APP片段和Aβ含量降低。β-分泌酶活性的抑制可能对AD的治疗具有重要意义。

Alzheimer's disease (AD) is the most common but complex and heterogenous genetic disorders of dementia. Neuropathology of brains affected with complex and heterogenous disorders of AD shows rather a homogenous feature. This inevitable fact simply indicates that accumulation and aggregation of Amyloid β(Aβ) is the primary cause of AD. Aβ is an about 40 amino acid residue peptide, derived, by two sequential cleavages, from APP. The proteases involved are β-secretase, as the novel aspartyl protease, beta-site APP cleaving enzyme (BACE), and γ-secretase, a multimeric complex containing the presenilins. It is quite reasonable that the balance between the generation and the degradation/clearance of Aβ might be altered in the brains affected with AD. Aβis a about 40 amino acid residue peptide, derived, by two sequential cleavages, from amyloid precursor protein (APP). The proteases involved are β-secretase, as the novel aspartyl protease, (BACE), and γ-secretase, a multimeric complex containing the presenillins.On the other hand, recently we have established an excellent experimental culture myocyte system under the presence or the absence of chloroquine (CQN) to study APP processing to generate Aβ. In this experiment, we have examined the balance between the generation and the degradation/clearance of Aβ. It is shown that BACE mRNA expression is up-regulated, and Aβ amount is increased under CQN treatment, and that antisense oligonucleotides for BACE treatments reduce the level of C99, β-secretase cleaved C-terminus APP fragment and Aβ level. The inhibition of β-secretase activity might have great therapeutic potential in AD treatment.