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Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease

机译：阿尔茨海默病中异常的蛋白水解加工和治疗策略

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摘要

Amyloid-beta peptide (Abeta) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Abeta is derived from amyloid-p precursor protein that is sequentially cleaved by two aspartate proteases, beta- and gamma-secretases. Secreted Abeta is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Abeta by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD, Thus, the dynamics of cerebral Abeta, called as "Abeta economy", would be the mechanistic basis of AD pathogenesis. Partial loss of gamma-secretase activity leads to the increased generation of toxic Ap isoforms, indicating that activation of gamma-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a beta-secretase enzyme, has emerged as a prime drug target for lowering brain Abeta levels. Recent studies revealed the decreased clearance of Abeta in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Abeta economy, and development of effective treatment and diagnostics for AD.
机译：淀粉样蛋白β肽（Abeta）和Tau分别是老年斑块和神经纤维缠结的主要成分，分别沉积在阿尔茨海默病（AD）患者的大脑中。 Abeta衍生自淀粉样蛋白-P前体蛋白，其被两种天冬氨酸蛋白酶，β-和γ-分泌酶顺序地切割。然后通过几种蛋白酶分解Abeta的分泌物。几种证据表明，通过增加产量或降低的降解积累ABETA诱导陶而道的神经元毒性和广告的症状表现，从而称为“ABETA经济”，将是广告的机械基础发病。 γ-分泌酶活性的部分丧失导致增加毒性AP同种型的产生，表明γ-分泌酶的激活将为AD提供有益效果。在广泛的发现和开发工作之后，BACE1是β-分泌酶，作为降低脑ABETA水平的主要药物靶标。最近的研究揭示了散发性AD患者的Abeta清除下调，表明分解代谢机制在广告发病机制中的重要性。我将与这些蛋白水解机制讨论参与Abeta经济监管，以及广告的有效治疗和诊断的发展。

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