Astrocyte-derived lactoferrin reduces β-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice
Astrocyte-derived lactoferrin reduces β-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice
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DOI：
10.1111/bph.16161
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发表时间：
2023-07-08
影响因子：
7.3
通讯作者：
Wang，Zhan-You
中科院分区：
文献类型：
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作者：
Fan，Yong-Gang;Guo，Chuang;Wang，Zhan-You
背景和目的在阿尔茨海默病（AD）患者的大脑中观察到星形细胞性乳铁蛋白（Lf）的过度表达，而星形细胞性Lf在AD进展中的作用尚未明确。在这项研究中，我们旨在评估星形细胞Lf对AD进展的影响。实验方法利用过表达人Lf的星形胶质细胞的雄性APP/PS1小鼠，研究星形胶质细胞Lf对AD进展的影响。N2a‐sw细胞也被用来进一步揭示星形细胞Lf对β‐淀粉样蛋白（Aβ）产生的机制。关键结果星形细胞Lf过表达增加APP/PS1小鼠蛋白磷酸酶2A （PP2A）活性，降低淀粉样蛋白前体蛋白（APP）磷酸化、Aβ负荷和tau过度磷酸化。在机制上，星形细胞Lf过表达促进了APP/PS1小鼠星形细胞Lf向神经元的摄取，而来自过表达Lf的星形细胞的条件培养基抑制了N2a‐sw细胞中p‐APP （Thr668）的表达。此外，重组人Lf （hLf）显著增强了PP2A活性并抑制了p - APP的表达，而抑制p38或PP2A活性则消除了hLf诱导的N2a - sw细胞中p - APP的下调。此外，hLf通过p38激活促进了p38和PP2A的相互作用，从而增强了PP2A的活性，低密度脂蛋白受体相关蛋白1 （LRP1）的敲低显著逆转了hLf诱导的p38激活和p - APP下调。sour数据提示星形胶质细胞Lf通过靶向LRP1促进神经元p38活化，随后促进p38与PP2A结合，增强PP2A酶活性，最终通过APP去磷酸化抑制Aβ的产生。总之，促进星形细胞Lf表达可能是一种潜在的抗AD策略。这篇文章是《从阿尔茨海默病到血管性痴呆：导致认知能力下降的不同途径》主题的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc
Background and PurposeOverexpression of astrocytic lactoferrin (Lf) was observed in the brain 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 ApproachMale APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a‐sw cells also were employed to further uncover the mechanism of astrocytic Lf on β‐amyloid (Aβ) production.Key ResultsAstrocytic 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 uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p‐APP (Thr668) expression in N2a‐sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p‐APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf‐induced p‐APP down‐regulation 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 down‐regulation.Conclusions and ImplicationsOur data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aβ production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD.LINKED ARTICLESThis article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc