Identification of truncated C‐terminal fragments of the Alzheimer’s disease amyloid protein precursor derived from sequential proteolytic pathways,Journal of Neurochemistry

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Identification of truncated C‐terminal fragments of the Alzheimer’s disease amyloid protein precursor derived from sequential proteolytic pathways
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-08-05 , DOI: 10.1111/jnc.15143
Sebastien Mosser _{1,

2} , Hermeto Gerber _{1,

2} , Patrick C Fraering _{1,

2}

Affiliation

Recent evidence supports the emerging hypothesis that the amyloid‐β precursor protein C‐terminal fragments (APP‐CTFs) and dysregulations in both their qualitative and quantitative productions may actively and directly contribute to the neuronal toxicity in early phases of Alzheimer's disease (AD). These new findings revealed the urgent needs and gaps in better understanding the metabolism and full spectrum of APP‐CTFs. In this study, we characterized by mass spectrometry the full patterns of APP‐CTFs in different cell types and in the brain of an AD APPPS1 mouse model. In these systems, we first discovered a series of 71–80 amino acids long N‐terminally truncated APP‐CTFs of unknown functions. We next demonstrated that these N‐terminally truncated APP‐CTFs are sequentially produced by the proteolytic processing of APP‐C80, by an as yet unidentified protease. Finally, these N‐terminally truncated APP‐CTFs are likely protein substrates recognized and processed by the γ‐secretase complex, leading to the production of N‐terminally truncated Aβ peptides. Together, our findings provide new insights into the metabolism of APP and offer potential new strategies to modulate the production of toxic Aβ peptides in AD.

中文翻译：

鉴定来自顺序蛋白水解途径的阿尔茨海默氏病淀粉样蛋白前体的截短的C末端片段

最近的证据支持新出现的假说，即淀粉样β蛋白前体蛋白C末端片段（APP-CTF）的定性和定量生成失调可能在阿尔茨海默氏病（AD）的早期阶段积极而直接地导致神经元毒性。这些新发现揭示了在更好地了解APP-CTF的代谢和全谱方面的迫切需求和差距。在这项研究中，我们通过质谱法对AD APPPS1小鼠模型的不同细胞类型和大脑中APP-CTF的完整模式进行了表征。在这些系统中，我们首先发现了一系列功能未知的N-端截短的APP-CTF，长度为71-80个氨基酸。接下来，我们证明了这些N末端截短的APP-CTF是通过APP-C80的蛋白水解过程顺序产生的，尚未被鉴定的蛋白酶。最后，这些N末端截短的APP-CTF可能是被γ-分泌酶复合物识别和加工的蛋白质底物，从而导致N末端截短的Aβ肽的产生。总之，我们的发现为APP的代谢提供了新见解，并提供了潜在的新策略来调节AD中有毒Aβ肽的产生。

更新日期：2020-08-05

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