Advanced Glycation End Products Modulate Amyloidogenic APP Processing and Tau Phosphorylation: A Mechanistic Link between Glycation and the Development of Alzheimer’s Disease,ACS Chemical Neuroscience

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Advanced Glycation End Products Modulate Amyloidogenic APP Processing and Tau Phosphorylation: A Mechanistic Link between Glycation and the Development of Alzheimer’s Disease
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-01-31 00:00:00 , DOI: 10.1021/acschemneuro.7b00410
Kedar Batkulwar _{1,

2} , Rashmi Godbole ₁ , Reema Banarjee _{1,

2} , Omar Kassaar ₃ , Robert J. Williams ₃ , Mahesh J. Kulkarni _{1,

2}

Affiliation

Advanced glycation end products (AGEs) are implicated in the pathology of Alzheimer’s disease (AD), as they induce neurodegeneration following interaction with the receptor for AGE (RAGE). This study aimed to establish a mechanistic link between AGE-RAGE signaling and AD pathology. AGE-induced changes in the neuro2a proteome were monitored by SWATH-MS. Western blotting and cell-based reporter assays were used to investigate AGE-RAGE regulated APP processing and tau phosphorylation in primary cortical neurons. Selected protein expression was validated in brain samples affected by AD. The AGE-RAGE axis altered proteome included increased expression of cathepsin B and asparagine endopeptidase (AEP), which mediated an increase in Aβ_1–42 formation and tau phosphorylation, respectively. Elevated cathepsin B, AEP, RAGE, and pTau levels were found in human AD brain, coincident with enhanced AGEs. This study demonstrates that the AGE-RAGE axis regulates Aβ_1–42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology.

中文翻译：

先进的糖基化终产物调节淀粉样蛋白APP加工和Tau磷酸化：糖化与阿尔茨海默氏病发展之间的机制联系

晚期糖基化终产物（AGEs）与阿尔茨海默氏病（AD）的病理学有关，因为它们在与AGE受体（RAGE）相互作用后诱导神经变性。这项研究旨在建立AGE-RAGE信号和AD病理之间的机制联系。通过SWATH-MS监测AGE诱导的Neuro2a蛋白质组变化。免疫印迹和基于细胞的报告基因检测被用于调查AGE-RAGE调节的APP处理和皮层神经元中tau磷酸化。在受AD影响的脑样本中验证了选定的蛋白表达。AGE-RAGE轴改变的蛋白质组包括组织蛋白酶B和天冬酰胺内肽酶（AEP）的表达增加，这介导了_Aβ1–42的增加形成和tau磷酸化。在人AD脑中发现组织蛋白酶B，AEP，RAGE和pTau水平升高，与AGEs升高同时发生。这项研究表明，AGE-RAGE轴通过增加组织蛋白酶B和AEP调节_Aβ1–42的形成和tau磷酸化，为AGEs和AD病理学之间提供了新的分子联系。

更新日期：2018-01-31

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