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Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus

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Abstract

An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer’s disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-β binding to RAGE, neurological damage and inflammation in the APPsw/0 transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood–brain barrier. In this study, an AGEs–RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs–RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.

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Abbreviations

AGEs:

Advanced glycation end products

APP:

Amyloid precursor protein

CAT:

Catalase

GR:

Glutathione reductase

GSH-Px:

Glutathione peroxidase

IL-1β:

Interleukin-1beta

MDA:

Malondialdehyde

RAGE:

AGEs receptor

ROSs:

Reactive oxygen species

SOD:

Superoxide dismutase

TNF-α:

Necrosis factor-α

References

  1. Ferrer I (2012) Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog Neurobiol 97(1):38–51

    Article  PubMed  Google Scholar 

  2. Verri M, Pastoris O, Dossena M (2011) Mitochondrial alterations, oxidative stress and neuroinflammation in Alzheimer’s disease. Int J Immunopathol Pharmacol 25(2):345–353

    Google Scholar 

  3. Takeuchi M, Kikuchi S, Sasaki N (2004) Involvement of advanced glycation end-products (AGEs) in Alzheimer’s disease. Curr Alzheimer Res 1(1):39–46

    Article  CAS  PubMed  Google Scholar 

  4. Ko SY, Lin YP, Lin YS (2010) Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species. Free Radic Biol Med 49(3):474–480

    Article  CAS  PubMed  Google Scholar 

  5. Choi BR, Cho WH, Kim J (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer’s disease. Exp Mol Med 46(2):e75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Srikanth V, Maczurek A, Phan T (2011) Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging 32(5):763–777

    Article  CAS  PubMed  Google Scholar 

  7. Koch M, Chitayat S, Dattilo BM (2010) Structural basis for ligand recognition and activation of RAGE. Structure 18(10):1342–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Franke S, Siggelkow H, Wolf G (2007) Advanced glycation endproducts influence the mRNA expression of RAGE, RANKL and various osteoblastic genes in human osteoblasts. Arch Physiol Biochem 113(3):154–161

    Article  CAS  PubMed  Google Scholar 

  9. Slowik A, Merres J, Elfgen A (2012) Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE)-and amyloid beta 1-42-induced signal transduction in glial cells. Mol Neurodegener 7(1):55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fang F, Lue LF, Yan S (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Aβ accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24(4):1043–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen CH, Zhou W, Liu S (2012) Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 15(1):77–90

    Article  CAS  PubMed  Google Scholar 

  12. Tobon-Velasco JC, Cuevas E, Torres-Ramos MA (2014) Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 13(9):1615–1626

    Article  CAS  PubMed  Google Scholar 

  13. Yan R, Vassar R (2014) Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13(3):319–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Deane R, Singh I, Sagare AP (2012) A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122(4):1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. JJ JJ, Cacabelos R (1998) β-Amyloid (1–40)-induced neurodegeneration in the rat hippocampal neurons of the CA1 subfield. Acta Neuropathol 95(5):455–465

    Article  Google Scholar 

  16. Hong Y, Hou L, Hou XY, Liu XP (2015) Ectogenic AGEs up-regulate amyloid-β in rat hippocampus through RAGE–CTGF pathway (in preparation)

  17. Collison KS, Makhoul NJ, Zaidi MZ (2012) Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity. PLoS ONE 7(4):e31570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Siqueira IR, Fochesatto C, da Silva Torres IL (2005) Aging affects oxidative state in hippocampus, hypothalamus and adrenal glands of Wistar rats. Life Sci 78(3):271–278

    Article  Google Scholar 

  19. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  PubMed  Google Scholar 

  20. Winterbourn CC, Hawkins R, Brian M (1975) The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85(2):337–341

    CAS  PubMed  Google Scholar 

  21. Jollow D, Mitchell J, Na Zampaglione (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11(3):151–169

    Article  CAS  PubMed  Google Scholar 

  22. Hafeman D, Sunde R, Hoekstra W (1974) Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat. J Nutr 104(5):580–587

    CAS  PubMed  Google Scholar 

  23. Arancio O, Zhang HP, Chen X (2004) RAGE potentiates Aβ-induced perturbation of neuronal function in transgenic mice. EMBO J 23(20):4096–4105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lan Z, Liu J, Chen L (2012) Danggui-Shaoyao-San ameliorates cognition deficits and attenuates oxidative stress-related neuronal apoptosis in d-galactose-induced senescent mice. J Ethnopharmacol 141(1):386–395

    Article  CAS  PubMed  Google Scholar 

  25. Cai ZY, Liu NN,Wang CL,Qin BY, Zhou YJ, Xiao M, Chang LY, Yan LJ, Zhao B (2015) Role of RAGE in Alzheimer’s disease. Cell Mol Neurobiol. doi:10.1007/s10571-015-0233-3

  26. Smith MA, Monnier VM, Sayre LM, Perry G (1995) Amyloidosis, advanced glycation end products and Alzheimer disease. NeuroReport 6:1595–1596

    Article  CAS  PubMed  Google Scholar 

  27. Thome J, Kornhuber J, Munch G, Schinzel R, Taneli Y, Zielke B, Rosler M, Riederer P (1996) New hypothesis on etiopathogenesis of Alzheimer syndrome. Advanced glycation end products (AGEs). Nervenarzt 67:924–929

    Article  CAS  PubMed  Google Scholar 

  28. Guglielmotto M, Aragno M, Tamagno E (2012) AGEs/RAGE complex upregulates BACE1 via NF-κB pathway activation. Neurobiol Aging 33(1):196.e113–196.e127

    Article  Google Scholar 

  29. Mincheva-Tasheva S, Soler RM (2013) NF-κB signaling pathways role in nervous system physiology and pathology. Neuroscientist 19(2):175–194

    Article  CAS  PubMed  Google Scholar 

  30. Bourne KZ, Ferrari DC, Lange-Dohna C (2007) Differential regulation of BACE1 promoter activity by nuclear factor-κB in neurons and glia upon exposure to β-amyloid peptides. J Neurosci Res 85(6):1194–1204

    Article  CAS  PubMed  Google Scholar 

  31. Paris D, Patel N, Quadros A (2007) Inhibition of Aβ production by NF-κB inhibitors. Neurosci Lett 415(1):11–16

    Article  CAS  PubMed  Google Scholar 

  32. Win MT, Yamamoto Y, Munesue S (2012) Regulation of RAGE for attenuating progression of diabetic vascular complications. Exp Diabetes Res 2012:894605

  33. Lander HM, Tauras JM, Ogiste JS (1997) Activation of the receptor for advanced glycation end products triggers a p21 ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272(28):17810–17814

    Article  CAS  PubMed  Google Scholar 

  34. Lue LF, Walker DG, Brachova L (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp Neurol 171(1):29–45

    Article  CAS  PubMed  Google Scholar 

  35. Deane R, Bell R, Sagare A (2009) Clearance of amyloid-β peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 8(1):16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith MA, Rottkamp CA, Nunomura A (2000) Oxidative stress in Alzheimer’s disease. Biochim Biophys Acta 1502(1):139–144

    Article  CAS  PubMed  Google Scholar 

  37. Gu Q, Wang B, Zhang XF, Ma YP (2014) Contribution of receptor for advanced glycation end products to vasculature-protecting effects of exercise training in aged rats. Eur J Pharmacol 741:186–194

    Article  CAS  PubMed  Google Scholar 

  38. Yin QQ, Dong CF, Dong SQ (2012) AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons. Cell Mol Neurobiol 32(8):1299–1309

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 30971036) and Shandong Provincial Natural Science Foundation of China (No. Y2008C13).

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    Authors and Affiliations

    1. Department of Senile Neurology, Provincial Hospital Affiliated to Shandong University, 324#, Jing Wu Road, Jinan, 250021, China

      Yan Hong, Chao Shen, Qingqing Yin, Menghan Sun, Yingjuan Ma & Xueping Liu

    2. Department of Anti-Aging, Provincial Hospital Affiliated to Shandong University, 324#, Jing Wu Road, Jinan, 250021, People’s Republic of China

      Xueping Liu

    3. Anti-Aging Monitoring Laboratory, Provincial Hospital Affiliated to Shandong University, 324#, Jing Wu Road, Jinan, 250021, People’s Republic of China

      Xueping Liu

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    1. Yan Hong
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    2. Chao Shen
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    3. Qingqing Yin
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    Correspondence to Xueping Liu.

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    Yan Hong and Chao Shen have contributed equally to this study.

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    Hong, Y., Shen, C., Yin, Q. et al. Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus. Neurochem Res 41, 1192–1199 (2016). https://doi.org/10.1007/s11064-015-1814-8

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