Atorvastatin Attenuates Cognitive Deficits and Neuroinflammation Induced by Aβ1–42 Involving Modulation of TLR4/TRAF6/NF-κB Pathway
- 275 Downloads
Inflammatory damage aggravates the progression of Alzheimer’s disease (AD) and the mechanism of inflammatory damage may provide a new therapeutic window for the treatment of AD. Toll-like receptor 4 (TLR4)-mediated signaling can regulate the inflammatory process. However, changes in TLR4 signaling pathway induced by beta-amyloid (Aβ) have not been well characterized in brain, especially in the hippocampus. In the present study, we explored the changes of TLR4 signaling pathway induced by Aβ in the hippocampus and the role of atorvastatin in modulating this signal pathway and neurotoxicity induced by Aβ. Experimental AD rats were induced by intrahippocampal injection of Aβ1–42, and the rats were treated with atorvastatin by oral gavage from 3 weeks before to 6 days after injections of Aβ1–42. To determine the spatial learning and memory ability of rats in the AD models, Morris water maze (MWM) was performed. The expression of the glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule-1 (Iba-1), TLR4, tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear transcription factor (NF)-κB (NF-κB) protein in the hippocampus was detected by immunohistochemistry and Western blot. Compared to the control group, increased expression of TLR4, TRAF6, and NF-κB was observed in the hippocampus at 7 days post-injection of Aβ (P < 0.01). Furthermore, atorvastatin treatment significantly ameliorated cognitive deficits of rats, attenuated microglia and astrocyte activation, inhibited apoptosis, and down-regulated the expression of TLR4, TRAF6, and NF-κB, both at the mRNA and protein levels (P < 0.01). TLR4 signaling pathway is thus actively involved in Aβ-induced neuroinflammation and atorvastatin treatment can exert the therapeutic benefits for AD via the TLR4 signaling pathway.
KeywordsAtorvastatin Alzheimer’s disease Protection TLR4 TRAF6 NF-κB
We gratefully acknowledge the technical support and helpful discussions of our colleagues and collaborators.
S.W. and X.W.Z. prepared the manuscript and were participated in the data analysis; L.Y.Z. was involved in the data analysis; X.N.S. and W.N.Z. collected data; H.S.C. and G.H.Z. designed this study and guided the data analysis. All authors have read and approved the final manuscript.
This work was supported by the Hebei Natural Science Foundation (C2011206110) and the Key Project of Hebei Medical Science Research (20150211). This work was supported by and conducted in the Hebei Key Laboratory for Neurology.
Compliance with Ethical Standards
Conflicts of Interest
The authors declare that they have no conflict of interest.
- Calvorodríguez M, Fuente CDL, Garcíadurillo M, Garcíarodríguez C, Villalobos C, Núñez L (2017) Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons. J Neuroinflammation 14(1):24. https://doi.org/10.1186/s12974-017-0802-0 CrossRefGoogle Scholar
- Cameron B, Tse W, Lamb R, Li X, Lamb BT, Landreth GE (2012) Loss of interleukin receptor associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s disease. J Neurosci 32(43):15112–15123. https://doi.org/10.1523/JNEUROSCI.1729-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
- Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Alabed Y, Davies P, Marambaud P (2012) Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J Neurochem 120(3):461–472. https://doi.org/10.1111/j.1471-4159.2011.07594.x CrossRefPubMedGoogle Scholar
- Castro AA, Wiemes BP, Matheus FC, Lapa FR, Viola GG, Santos AR, Tasca CI, Prediger RD (2013) Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats, an experimental model of Parkinson’s disease. Brain Res 1513:103–116. https://doi.org/10.1016/j.brainres.2013.03.029 CrossRefPubMedGoogle Scholar
- Cibickova L, Hyspler R, Micuda S, Cibicek N, Zivna H, Jun D, Ticha A, Brcakova E, Palicka V (2009) The influence of simvastatin, atorvastatin and high-cholesterol diet on acetylcholinesterase activity, amyloid beta and cholesterol synthesis in rat brain. Steroids 74(1):13–19. https://doi.org/10.1016/j.steroids.2008.08.007 CrossRefPubMedGoogle Scholar
- Clarke RM, O'Connell F, Lyons A, Lynch MA (2007) The HMG-CoA reductase inhibitor, atorvastatin, attenuates the effects of acute administration of amyloid-beta1-42 in the rat hippocampus in vivo. Neuropharmacology 52(1):136–145. https://doi.org/10.1016/j.neuropharm.2006.07.031 CrossRefPubMedGoogle Scholar
- Kurata T, Kawai H, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y, Abe K (2012) Statins have therapeutic potential for the treatment of Alzheimer’s disease, likely via protection of the neurovascular unit in the AD brain. J Neurol Sci 322(1-2):59–63. https://doi.org/10.1016/j.jns.2012.06.011 CrossRefPubMedGoogle Scholar
- Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30(5):759–768. https://doi.org/10.1016/j.neurobiolaging.2007.08.018 CrossRefPubMedGoogle Scholar
- Lyons A, Murphy KJ, Clarke R, Lynch MA (2011) Atorvastatin prevents age-related and amyloid-β-induced microglial activation by blocking interferon-γ release from natural killer cells in the brain. J Neuroinflammation 8(1):27. https://doi.org/10.1186/1742-2094-8-27 CrossRefPubMedPubMedCentralGoogle Scholar
- Murphy MP, Morales J, Beckett TL, Astarita G, Piomelli D, Weidner A, Studzinski CM, Dowling AL, Wang X, Levine H 3rd, Kryscio RJ, Lin Y, Barrett E, Head E (2010) Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs. J Alzheimers Dis 22(1):135–150. https://doi.org/10.3233/JAD-2010-100639 CrossRefPubMedGoogle Scholar
- Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates—the new coronal set. Mouse Brain Stereotaxic Coordinates 28:6Google Scholar
- Piermartiri TC et al (2010) Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β 1–40 administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 226(2):274–284. https://doi.org/10.1016/j.expneurol.2010.08.030 CrossRefPubMedGoogle Scholar
- Russo I, Caracciolo L, Tweedie D, Choi SH, Greig NH, Barlati S, Bosetti F (2012) 3,6′-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. J Neurochem 122(6):1181–1192. https://doi.org/10.1111/j.1471-4159.2012.07846.x CrossRefPubMedPubMedCentralGoogle Scholar
- Schmole AC et al (2015) Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer’s disease mouse model. Neurobiol Aging 36(2):710–719. https://doi.org/10.1016/j.neurobiolaging.2014.09.019 CrossRefPubMedGoogle Scholar
- 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(1):203–211. https://doi.org/10.1016/j.intimp.2015.03.029 CrossRefPubMedGoogle Scholar
- Shi S, Liang D, Chen Y, Xie Y, Wang Y, Wang L, Wang Z, Qiao Z (2016) Gx-50 reduces β-amyloid-induced TNF-α, IL-1β, NO, and PGE2 expression and inhibits NF-κB signaling in a mouse model of Alzheimer’s disease. Eur J Immunol 46(3):665–676. https://doi.org/10.1002/eji.201545855 CrossRefPubMedGoogle Scholar
- Smith KB, Kang P, Sabbagh MN (2017) The effect of statins on rate of cognitive decline in mild cognitive impairment. Alzheimers Dement 3:149–156Google Scholar
- Song M, Jin JJ, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K (2011) TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8(1):92. https://doi.org/10.1186/1742-2094-8-92 CrossRefPubMedPubMedCentralGoogle Scholar
- Tang SS, Hong H, Chen L, Mei Z, Ji M, Xiang G, Li N, Ji H (2014) Involvement of cysteinyl leukotriene receptor 1 in Aβ1-42-induced neurotoxicity in vitro and in vivo. Neurobiol Aging 35(3):590–599. https://doi.org/10.1016/j.neurobiolaging.2013.09.036 CrossRefPubMedGoogle Scholar
- Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR, Arumugam TV, Mattson MP (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213(1):114–121. https://doi.org/10.1016/j.expneurol.2008.05.014 CrossRefPubMedPubMedCentralGoogle Scholar
- Zaghi GG, Godinho J, Ferreira ED, Ribeiro MH, Previdelli IS, de Oliveira RM, Milani H (2016) Robust and enduring atorvastatin-mediated memory recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats. Prog Neuro-Psychopharmacol Biol Psychiatry 65:179–187. https://doi.org/10.1016/j.pnpbp.2015.10.004 CrossRefGoogle Scholar
- Zhang J, Fu B, Zhang X, Chen L, Zhang L, Zhao X, Bai X, Zhu C, Cui L, Wang L (2013) Neuroprotective effect of bicyclol in rat ischemic stroke: down-regulates TLR4, TLR9, TRAF6, NF-κB, MMP-9 and up-regulates claudin-5 expression. Brain Res 1528:80–88. https://doi.org/10.1016/j.brainres.2013.06.032 CrossRefPubMedGoogle Scholar
- Zhang L, Sui H, Liang B, Wang H, Qu W, Yu S, Jin Y (2014) Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway. Acta Pharmacol Sin 35(6):716–726. https://doi.org/10.1038/aps.2013.203 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhao BS, Liu Y, Gao XY, Zhai HQ, Guo JY, Wang XY (2014) Effects of ginsenoside Rg1 on the expression of toll-like receptor 3, 4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line. Molecules 19(10):16925–16936. https://doi.org/10.3390/molecules191016925 CrossRefPubMedGoogle Scholar