Department of Public Health and Primary Care, Institute of Public Health, Forvie Site University of Cambridge, School of Clinical Medicine, Cambridge, UK.
Mol Psychiatry. 2018 Jan;23(1):81-93. doi: 10.1038/mp.2017.218. Epub 2017 Nov 7.
Many models of disease progression in Alzheimer's disease (AD) have been proposed to help guide experimental design and aid the interpretation of results. Models focussing on the genetic evidence include the amyloid cascade (ACH) and presenilin (PSH) hypotheses and the amyloid precursor protein (APP) matrix approach (AMA), of which the ACH has held a dominant position for over two decades. However, the ACH has never been fully accepted and has not yet delivered on its therapeutic promise. We review the ACH, PSH and AMA in relation to levels of APP proteolytic fragments reported from AD-associated mutations in APP. Different APP mutations have diverse effects on the levels of APP proteolytic fragments. This evidence is consistent with at least three disease pathways that can differ between familial and sporadic AD and two pathways associated with cerebral amyloid angiopathy. We cannot fully evaluate the ACH, PSH and AMA in relation to the effects of mutations in APP as the APP proteolytic system has not been investigated systematically. The confounding effects of sequence homology, complexity of competing cleavages and antibody cross reactivities all illustrate limitations in our understanding of the roles these fragments and the APP proteolytic system as a whole in normal aging and disease play. Current experimental design should be refined to generate clearer evidence, addressing both aging and complex disorders with standardised reporting formats. A more flexible theoretical framework capable of accommodating the complexity of the APP proteolytic system is required to integrate available evidence.
许多阿尔茨海默病（AD）疾病进展模型被提出，以帮助指导实验设计和辅助结果解释。关注遗传证据的模型包括淀粉样蛋白级联（ACH）和早老素（PSH）假说以及淀粉样前体蛋白（APP）基质方法（AMA），其中 ACH 占据主导地位已超过二十年。然而，ACH 从未被完全接受，也未能兑现其治疗承诺。我们回顾了 ACH、PSH 和 AMA 与 APP 相关突变报告的 AD 相关 APP 蛋白水解片段水平的关系。不同的 APP 突变对 APP 蛋白水解片段的水平有不同的影响。这一证据与至少三种疾病途径一致，这些途径在家族性和散发性 AD 之间存在差异，与脑淀粉样血管病相关的两种途径。我们不能完全评估 ACH、PSH 和 AMA 与 APP 突变的影响，因为 APP 蛋白水解系统尚未得到系统研究。序列同源性、竞争裂解的复杂性以及抗体交叉反应性的混杂影响都说明了我们对这些片段和 APP 蛋白水解系统作为一个整体在正常衰老和疾病中的作用的理解存在局限性。目前的实验设计应该得到改进，以生成更清晰的证据，用标准化的报告格式同时解决衰老和复杂疾病。需要一个更灵活的理论框架来容纳 APP 蛋白水解系统的复杂性，以整合现有证据。
