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

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

References

  1. 1.

    Ono K (2018) Alzheimer’s disease as oligomeropathy. Neurochem Int 119:57–70

    CAS  PubMed  Google Scholar 

  2. 2.

    Salinaro AT, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, Ontario ML, Tomasello M et al (2018) Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms. Immun Ageing 15:8

    Google Scholar 

  3. 3.

    Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB (2014) Neuroinflammation in the pathogenesis of Alzheimer’s disease A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8:112

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Woo JH, Lee JH, Kim H, Park SJ, Joe EH, Jou I (2015) Control of inflammatory responses: a new paradigm for the treatment of chronic neuronal diseases. Exp Neurobiol 24:95–102

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353:777–783

    CAS  PubMed  Google Scholar 

  6. 6.

    Wang S, Zhang X, Zhai L, Sheng X, Zheng W, Chu H, Zhang G (2018) Atorvastatin attenuates cognitive deficits and neuroinflammation induced by A beta(1-42) involving modulation of TLR4/TRAF6/NF-kappa B pathway. J Mol Neurosci 64:363–373

    CAS  PubMed  Google Scholar 

  7. 7.

    Muhammad T, Ikram M, Ullah R, Rehman SU, Kim MO (2019) Hesperetin, a citrus flavonoid, attenuates LPS-induced neuroinflammation, apoptosis, and memory impairments by modulating TLR4/NF-kappaB signaling. Nutrients 11:648

    CAS  PubMed Central  Google Scholar 

  8. 8.

    Dilshara MG, Lee KT, Jayasooriya RGPT, Kang CH, Park SR, Choi YH, Choi IW, Hyun JW et al (2014) Downregulation of NO and PGE(2) in LPS-stimulated BV2 microglial cells by trans-isoferulic acid via suppression of PI3K/Akt-dependent NF-kappa B and activation of Nrf2-mediated HO-1. Int Immunopharmacol 18:203–211

    CAS  PubMed  Google Scholar 

  9. 9.

    Park HY, Kim TH, Kim CG, Kim GY, Kim CM, Kim ND, Kim BW, Hwang HJ et al (2013) Purpurogallin exerts anti-inflammatory effects in lipopolysaccharide-stimulated BV2 microglial cells through the inactivation of the NF-kappa B and MAPK signaling pathways. Int J Mol Med 32:1171–1178

    PubMed  Google Scholar 

  10. 10.

    De Vita T, Albani C, Realin N, Migliore M, Basit A, Ottonello G, Cavalli A (2019) Inhibition of serine palmitoyltransferase by a small organic molecule promotes neuronal survival after astrocyte amyloid beta 1-42 injury. ACS Chem Neurosci 10:1627–1635

    PubMed  Google Scholar 

  11. 11.

    Seok SM, Park TY, Park HS, Baik EJ, Lee SH (2015) Fructose-1,6-bisphosphate suppresses lipopolysaccharide-induced expression of ICAM-1 through modulation of toll-like receptor-4 signaling in brain endothelial cells. Int Immunopharmacol 26:203–211

    CAS  PubMed  Google Scholar 

  12. 12.

    Xia W, Luo P, Hua P, Ding P, Li C, Xu J, Zhou H, Gu Q (2019) Discovery of a new pterocarpan-type antineuroinflammatory compound from Sophora tonkinensis through suppression of the TLR4/NF kappa B/MAPK signaling pathway with PUI as a potential target. ACS Chem Neurosci 10:295–303

    CAS  PubMed  Google Scholar 

  13. 13.

    Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA (2003) Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 112:1533–1540

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    May P, Rohlmann A, Bock HH, Zurhove K, Marth JD, Schomburg ED, Noebels JL, Beffert U et al (2004) Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. Mol Cell Biol 24:8872–8883

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chuang TY, Guo Y, Seki SM, Rosen AM, Johanson DM, Mandell JW, Lucchinetti CF, Gaultier A (2016) LRP1 expression in microglia is protective during CNS autoimmunity. Acta Neuropathol Commun 4:UNSP 68

    Google Scholar 

  16. 16.

    Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan FR, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–457

    CAS  PubMed  Google Scholar 

  17. 17.

    Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L et al (2007) Amyloid precursor protein regulates brain apolipoprotein e and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 56:66–78

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK (2008) LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev 88:887–918

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Liu CC, Hu J, Zhao N, Wang J, Wang N, Cirrito JR, Kanekiyo T, Holtzman DM et al (2017) Astrocytic LRP1 mediates brain a beta clearance and impacts amyloid deposition. J Neurosci 37:4023–4031

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Van Acker ZP, Bretou M, Annaert W (2019) Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors. Mol Neurodegener 14:20

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Wujak L, Schnieder J, Schaefer L, Wygrecka M (2018) LRP1: a chameleon receptor of lung inflammation and repair. Matrix Biol 68–69:366–381

    PubMed  Google Scholar 

  22. 22.

    Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, Han X, Weeber EJ et al (2010) Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci 30:17068–17078

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Mantuano E, Brifault C, Lam MS, Azmoon P, Gilder AS, Gonias SL (2016) LDL receptor-related protein-1 regulates NF kappa B and microRNA-155 in macrophages to control the inflammatory response. Proc Natl Acad Sci U S A 113:1369–1374

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    May P, Bock HH, Nofer JR (2013) Low density receptor-related protein 1 (LRP1) promotes anti-inflammatory phenotype in murine macrophages. Cell Tissue Res 354:887–889

    CAS  PubMed  Google Scholar 

  25. 25.

    Schubert K, Collins LE, Green P, Nagase H, Troeberg L (2019) LRP1 controls TNF release via the TIMP-3/ADAM17 axis in endotoxin-activated macrophages. J Immunol 202:1501–1509

    CAS  PubMed  Google Scholar 

  26. 26.

    Gaultier A, Arandjelovic S, Li X, Janes J, Dragojlovic N, Zhou GP, Dolkas J, Myers RR et al (2008) A shed form of LDL receptor-related protein-1 regulates peripheral nerve injury and neuropathic pain in rodents. Eur J Clin Investig 118:161–172

    CAS  Google Scholar 

  27. 27.

    Yang L, Liu CC, Zheng H, Kanekiyo T, Atagi Y, Jia L, Wang D, N'Songo A et al (2016) LRP1 modulates the microglial immune response via regulation of JNK and NF-kappa B signaling pathways. J Neuroinflamm 13:304

    Google Scholar 

  28. 28.

    Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S (2016) Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature 531:508–512

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS, Gus LZ, Wang HF et al (2014) Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 39:2949–2962

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Jiang T, Tan L, Zhu XC, Zhou JS, Cao L, Tan MS, Wang HF, Chen Q et al (2015) Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol Aging 36:3176–3186

    CAS  PubMed  Google Scholar 

  31. 31.

    Dodart JC, Marr RA, Koistinaho M, Gregersen BM, Malkani S, Verma IM, Paul SM (2005) Gene delivery of human apolipoprotein E alters brain beta burden in a mouse model of Alzheimers disease. Proc Natl Acad Sci U S A 102:1211–1216

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zhao WX, Zhang JH, Cao JB, Wang W, Wang DX, Zhang XY, Yu J, Zhang YY et al (2017) Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity. J Neuroinflamm 14:17

    Google Scholar 

  33. 33.

    Liu C, Wu YX, Zha S, Liu MP, Wang Y, Yang GD, Ma KG, Fei YL et al (2016) Treatment effects of tanshinone IIA against ntracerebroventricular streptozotocin-induced memory deficits in mice. Brain Res 1631:137–146

    CAS  PubMed  Google Scholar 

  34. 34.

    Shi Y, Huang W, Wang Y, Zhang R, Hou L, Xu J, Qiu Z, Xie Q et al (2018) (9)-(−)-Meptazinol, a novel dual-binding AChE inhibitor, rescues cognitive deficits and pathological changes in APP/PS1 transgenic mice. Transl Neurodegener 7:21

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Yang WN, Zhang JS, Shi LL, Ji SF, Yang XH, Zhai WY, Zong HF, Qian YH (2019) Protective effects of tanshinone IIA on SH-SY5Y cells against oA beta(1-42)-induced apoptosis due to prevention of endoplasmic reticulum stress. Int J Biochem Cell Biol 107:82–91

    CAS  PubMed  Google Scholar 

  36. 36.

    Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z, Huang J, Xu B et al (2018) Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun 69:351–363

    CAS  PubMed  Google Scholar 

  37. 37.

    Fu AKY, Hung KW, Yuen MYF, Zhou X, Mak DSY, Chan ICW, Cheung TH, Zhang B et al (2016) IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A 113:E2705–E2713

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R (2018) Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflamm 15:276

    Google Scholar 

  39. 39.

    Liu Y, Zhang Y, Zheng X, Fang T, Yang X, Luo X, Guo A, Newell KA et al (2018) Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice. J Neuroinflamm 15:112

    Google Scholar 

  40. 40.

    Ruzicka J, Urdzikova LM, Svobodova B, Amin AG, Karova K, Dubisova J, Zaviskova K, Kubinova S et al (2018) Does combined therapy of curcumin and epigallocatechin gallate have a synergistic neuroprotective effect against spinal cord injury? Neural Regen Res 13:119–127

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Silverberg GD, Messier AA, Miller MC, Machan JT, Majmudar SS, Stopa EG, Donahue JE, Johanson CE (2010) Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging. J Neuropathol Exp Neurol 69:1034–1043

    CAS  PubMed  Google Scholar 

  42. 42.

    Shinohara M, Fujioka S, Murray ME, Wojtas A, Baker M, Rovelet-Lecrux A, Rademakers R, Das P et al (2014) Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease. Brain 137:1533–1549

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Wagner SL, Troncoso JC et al (2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest 106:1159–1166

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Bell RD, Deane R, Chow N, Long X, Sagare A, Singh I, Streb JW, Guo H et al (2009) SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol 11:143–U83

    CAS  PubMed  Google Scholar 

  45. 45.

    Hsieh YH, Deng JS, Chang YS, Huang GJ (2018) Ginsenoside Rh2 ameliorates lipopolysaccharide-induced acute lung injury by regulating the TLR4/PI3K/Akt/mTOR, Raf-1/MEK/ERK, and Keap1/Nrf2/HO-1 signaling pathways in mice. Nutrients 10:E1208

    PubMed  Google Scholar 

  46. 46.

    Deane R, Wu ZH, Sagare A, Davis J, Yan SD, Hamm K, Xu F, Parisi M et al (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of A beta isoforms. Neuron 43:333–344

    CAS  PubMed  Google Scholar 

  47. 47.

    Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N et al (2007) Role of the toll-like receptor 4 in neuro-inflammation in Alzheimer’s disease. Cell Physiol Biochem 20:947–956

    CAS  PubMed  Google Scholar 

  48. 48.

    Jeong J, Pandey S, Li Y, Badger JD, Lu W, Roche KW (2019) PSD-95 binding dynamically regulates NLGN1 trafficking and function. Proc Natl Acad Sci U S A 116:12035–12044

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Guarnieri FC, Pozzi D, Raimondi A, Fesce R, Valente MM, Delvecchio VS, Van Esch H, Matteoli M et al (2017) A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility. Hum Mol Genet 26:4699–4714

    CAS  PubMed  Google Scholar 

  50. 50.

    Head E, Corrada MM, Kahle-Wrobleski K, Kim RC, Sarsoza F, Goodus M, Kawas CH (2009) Synaptic proteins, neuropathology and cognitive status in the oldest-old. Neurobiol Aging 30:1125–1134

    CAS  PubMed  Google Scholar 

  51. 51.

    Whitfield DR, Vallortigara J, Alghamdi A, Howlett D, Hortobagyi T, Johnson M, Attems J, Newhouse S et al (2014) Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer’s disease: association with cognitive impairment. Neurobiol Aging 35:2836–2844

    CAS  PubMed  Google Scholar 

  52. 52.

    Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G et al (2003) Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 60:1495–1500

    CAS  PubMed  Google Scholar 

  53. 53.

    Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 218:167–179

    Google Scholar 

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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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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). https://doi.org/10.1007/s12035-020-01982-7

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Keywords

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