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


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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Alzheimer’s disease




Blood-brain barrier


Glial fibrillary acidic protein


Ionized calcium-binding adapter molecule 1


Low-density lipoprotein receptor-related protein 1








Mitogen-activated protein kinases


Morris water maze


Myeloid differentiation primary response protein 88


Neurofibrillary tangles


Nuclear factor-kappa B


Toll-like receptor 4


Tumor necrosis factor-α


Tumor necrosis factor receptor-associated factor 6


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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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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 (2020).

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  • Alzheimer’s disease
  • Low-density lipoprotein receptor-related protein 1
  • Toll-like receptor 4
  • Nuclear factor-kappa B
  • Mitogen-activated protein kinases