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Astrocyte-derived lactoferrin reduces Aβ burden by promoting the interaction of p38 and PP2A in APP/PS1 transgenic mice
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  • Yong-Gang Fan,
  • Chuang Guo,
  • Ling-Xiao Zhao,
  • Ri-Le Ge,
  • Zhong-Qiu Pang,
  • Da-Long He,
  • Hang Ren,
  • Yan-Hui Zhang,
  • Zhan-You Wang
Yong-Gang Fan
China Medical University
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Chuang Guo
Northeastern University
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Ling-Xiao Zhao
China Medical University
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Ri-Le Ge
China Medical University
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Zhong-Qiu Pang
Northeastern University
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Da-Long He
China Medical University
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Hang Ren
China Medical University
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Yan-Hui Zhang
China Medical University
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Zhan-You Wang
China Medical University

Corresponding Author:wangzy@cmu.edu.cn

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Abstract

Background and Purpose: Overexpression of astrocytic lactoferrin (Lf) was observed in the brains of Alzheimer’s disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. Experimental Approach: The APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression, and the N2a-sw cells were employed to further uncover the mechanism of astrocytic Lf on β-amyloid (Aβ) production. Key Results: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity, and reduced amyloid precursor protein (APP) phosphorylation, Aβ burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the astrocytic Lf secretion into neurons in APP/PS1 mice, and the conditional medium from astrocytes overexpressing Lf inhibited the p-APP(Thr668) expression in N2a-sw cells. Furthermore, the recombinant human Lf (hLf) also significantly enhanced PP2A activity and inhibited p-APP expression, while inhibitions of p38 or PP2A activities abrogated the hLf-induced p-APP downregulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity; and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP downregulation. Conclusions and Implications: Our data suggested that astrocytic Lf promoted neuronal p38 activation via targeting to LRP1, subsequently promoting p38 binds to PP2A to enhance PP2A activity, which finally inhibited Aβ production via APP dephosphorylation. Therefore, promoting astrocytic Lf expression may be a potential strategy against AD.
23 Nov 2022Submitted to British Journal of Pharmacology
15 Dec 2022Assigned to Editor
15 Dec 2022Submission Checks Completed
15 Dec 2022Review(s) Completed, Editorial Evaluation Pending
20 Dec 2022Reviewer(s) Assigned
11 Feb 2023Editorial Decision: Revise Minor