Tang Bor Luen
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore.
Brain Sci. 2020 Feb 22;10(2):122. doi: 10.3390/brainsci10020122.
Amyloid β (Aβ) peptides generated via sequential β- and γ-secretase processing of the amyloid precursor protein (APP) are major etiopathological agents of Alzheimer's disease (AD). However, an initial APP cleavage by an α-secretase, such as the a disintegrin and metalloproteinase domain-containing protein ADAM10, precludes β-secretase cleavage and leads to APP processing that does not produce Aβ. The latter appears to underlie the disease symptom-attenuating effects of a multitude of experimental therapeutics in AD animal models. Recent work has indicated that an endogenous inhibitor of ADAM10, secreted-frizzled-related protein 1 (SFRP1), is elevated in human AD brains and associated with amyloid plaques in mouse AD models. Importantly, genetic or functional attenuation of SFRP1 lowered Aβ accumulation and improved AD-related histopathological and neurological traits. Given SFRP1's well-known activity in attenuating Wnt signaling, which is also commonly impaired in AD, SFRP1 appears to be a promising therapeutic target for AD. This idea, however, needs to be addressed with care because of cancer enhancement potentials resulting from a systemic loss of SFRP1 activity, as well as an upregulation of ADAM10 activity. In this focused review, I shall discuss α-secretase-effected APP processing in AD with a focus on SFRP1, and explore the contrasting perspectives arising from the recent findings.
淀粉样前体蛋白（APP）经β-分泌酶和γ-分泌酶依次加工产生的淀粉样β（Aβ）肽是阿尔茨海默病（AD）的主要病因病理因子。然而，APP被α-分泌酶（如含去整合素和金属蛋白酶结构域的蛋白ADAM10）进行初始切割后，会阻止β-分泌酶的切割，并导致APP加工过程中不产生Aβ。后者似乎是多种实验性治疗药物在AD动物模型中减轻疾病症状作用的基础。最近的研究表明，ADAM10的内源性抑制剂分泌型卷曲相关蛋白1（SFRP1）在人类AD大脑中升高，并与小鼠AD模型中的淀粉样斑块相关。重要的是，SFRP1的基因或功能减弱可降低Aβ的积累，并改善与AD相关的组织病理学和神经学特征。鉴于SFRP1在减弱Wnt信号传导方面的众所周知的活性（Wnt信号传导在AD中也通常受损），SFRP1似乎是AD的一个有前景的治疗靶点。然而，由于SFRP1活性的全身性丧失以及ADAM10活性的上调会导致癌症增强的可能性，这个想法需要谨慎对待。在这篇重点综述中，我将讨论AD中α-分泌酶影响的APP加工，重点是SFRP1，并探讨近期研究结果中出现的不同观点。
