title: Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model.
abstract: Amyloid-beta (Aβ) deposition plays a crucial role in the progression of Alzheimer's disease (AD). The Aβ deposited extracellularly can be phagocytosed and degraded by surrounding activated astrocytes, but the precise mechanisms underlying Aβ clearance mediated by astrocytes remain unclear. In this study, we performed tandem mass tag-based quantitative proteomic analysis on the cerebral cortices of 5-month-old APP/PS1 double-transgenic mice. Among the 2668 proteins quantified, 35 proteins were upregulated and 12 were downregulated, with most of these proteins being shown here for the first time to be differently expressed in the APP/PS1 mouse. The altered proteins were involved in molecular transport, lipid metabolism, autophagy, inflammation, and oxidative stress. One specific protein, PEA15 (phosphoprotein enriched in astrocytes 15 kDa) upregulated in APP/PS1 mice, was verified to play a critical role in astrocyte-mediated Aβ phagocytosis. Furthermore, PEA15 levels were determined to increase with age in APP/PS1 mice, indicating that Aβ stimulated the upregulation of PEA15 in the APP/PS1 mouse. These results highlight the function of PEA15 in astrocyte-mediated Aβ phagocytosis, and thus provide novel insight into the molecular mechanism underlying Aβ clearance. The protein-expression profile revealed here should offer new clues to understand the pathogenesis of AD and potential therapeutic targets for AD.
  
  
  CONCLUSIONS
  Activated astrocytes are known to clear the Aβ deposited in the extracellular milieu, which is why they play a key role in regulating the progression of Alzheimer's disease (AD). However, the molecular mechanism underlying astrocyte-mediated Aβ phagocytosis and degradation remains unclear. By performing tandem mass tag-based quantitative proteomic analysis, we identified 47 proteins that were differentially expressed in APP/PS1 double-transgenic. To our knowledge, this is the first time most of these proteins have been reported to exhibit altered expression in the mouse model of AD. Furthermore, our results indicate that one of the proteins upregulated in the APP/PS1 mouse, PEA15 (phosphoprotein enriched in astrocytes 15 kDa), regulates astroglial phagocytosis of Aβ. Our findings provide new insights into the molecular mechanism underlying Aβ clearance in AD. The altered profile of protein expression in APP/PS1 mice described here should offer valuable clues to understand the pathogenesis of AD and facilitate the identification of potential targets for the treatment of AD.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: lujn100@126.com.
authors.forename: Junniao
authors.initials: J
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: mashuaipeng1986@126.com.
authors.forename: Shuaipeng
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: xuefei.zhang10@gmail.com.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: joanna0523@foxmail.com.
authors.forename: Liangjun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: mayuanhui31@gmail.com.
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Institute of Systems Biomedicine, Peking University, Beijing 100191, China. Electronic address: zhao-xu-yang@163.com.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: National Center for Nanoscience and Technology, Beijing 100190, China. Electronic address: laiwenjia1985@hotmail.com.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: hyshen85@163.com.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: wangqingsong@pku.edu.cn.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Electronic address: jijg@pku.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D010449:Peptide Mapping / Q000379:methods; D010587:Phagocytosis; D010750:Phosphoproteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D020543:Proteome
keywords: APP/PS1 mouse; Alzheimer's disease; Aβ; PEA15; Phagocytosis; Quantitative proteomics