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Silencing of LRP1 Exacerbates Inflammatory Response Via TLR4/NF-κB/MAPKs Signaling Pathways in APP/PS1 Transgenic Mice

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Abstract

Activation of glial cells (including microglia and astrocytes) appears central to the initiation and progression of neuroinflammation in Alzheimer’s disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for amyloid-β (Aβ), which plays a critical role in AD pathogenesis. LRP1 regulates inflammatory response by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on microglia- and astrocytic cell-mediated neuroinflammation and their underlying mechanisms in AD remain unclear. Therefore, using APP/PS1 transgenic mice, we found that LRP1 is downregulated during disease progression. Silencing of brain LRP1 markedly exacerbated AD-related neuropathology including Aβ deposition, neuroinflammation, and synaptic and neuronal loss, which was accompanied by a decline in spatial cognitive ability. Further mechanistic study revealed that silencing of LRP1 initiated neuroinflammation by increasing microgliosis and astrogliosis, enhancing pro-inflammatory cytokine production, and regulating toll-like receptor 4 (TLR4)-mediated activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Taken together, these findings indicated that LRP1 suppresses microglia and astrocytic cell activation by modulating TLR4/NF-κB/MAPK signaling pathways. Our results further provide insights into the role of LRP1 in AD pathogenesis and highlight LRP1 as a potential therapeutic target for the treatment of AD.

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Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

BBB:

Blood-brain barrier

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium-binding adapter molecule 1

LRP1:

Low-density lipoprotein receptor-related protein 1

LPS:

Lipopolysaccharide

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

MAPKs:

Mitogen-activated protein kinases

MWM:

Morris water maze

MyD88:

Myeloid differentiation primary response protein 88

NFTs:

Neurofibrillary tangles

NF-κB:

Nuclear factor-kappa B

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α

TRAF6:

Tumor necrosis factor receptor-associated factor 6

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Funding

This work was supported by the Natural Science Basic Research Plan in Shaanxi Province of China (2018JM7056); China Postdoctoral Science Foundation (2017T100758, 2016M590955); Postdoctoral Science Foundation of Shaanxi Province (2016BSHYDZZ04); Undergraduates Innovating Experiment Project of Nation (GJ201910698164); Undergraduates Innovating Experiment Project of Shaanxi Province (SJ201910698089); and Natural Science Foundation of China (81500928, 81571251).

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Authors and Affiliations

  1. Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061, Shaanxi province, China

    Yingying He, John Bosco Ruganzu, Quzhao Zheng, Xiangyuan Wu, Hui Jin, Xiaoqian Peng, Bo Ding, Chengheng Lin, Shengfeng Ji, Yanbing Ma & Weina Yang

  2. Medical Undergraduates of Xi’an Jiaotong University Health Science Center, Xi’an, China

    Quzhao Zheng, Xiangyuan Wu, Bo Ding & Chengheng Lin

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  1. Yingying He
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  2. John Bosco Ruganzu
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  3. Quzhao Zheng
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  4. Xiangyuan Wu
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  10. Yanbing Ma
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Contributions

WNY, YYH, JBR, and XQP designed the research, performed the majority of the experiments, and wrote the paper. BD, CHL, XYW, SFJ, and YBM performed the behavior experiments and interpreted the results. QZZ and HJ interpreted the results and gave technical support. All authors read and approved the final manuscript.

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Correspondence to Weina Yang.

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He, Y., Ruganzu, J.B., Zheng, Q. et al. Silencing of LRP1 Exacerbates Inflammatory Response Via TLR4/NF-κB/MAPKs Signaling Pathways in APP/PS1 Transgenic Mice. Mol Neurobiol 57, 3727–3743 (2020). https://doi.org/10.1007/s12035-020-01982-7

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