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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2013

Open Access 01-12-2013 | Research

Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’s disease mice model

Authors: Peng Jin, Jin-A Kim, Dong-Young Choi, Young-Jung Lee, Heon Sang Jung, Jin Tae Hong

Published in: Journal of Neuroinflammation | Issue 1/2013

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Abstract

Background

Alzheimer’s disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) fibrils within the brain and activation of astrocytes and microglial cells. In this study, we examined anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal (HPB242), an anti-inflammatory compound produced by the tyrosine-fructose Maillard reaction.

Methods

12-month-old Tg2576 mice were treated with HPB242 (5 mg/kg) for 1 month and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, western blot analysis, Gel electromobility shift assay, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains of Tg2576 mice. The Morris water maze task was analyzed using two-way ANOVA with repeated measures. Otherwise were analyzed by one-way ANOVA followed by Dunnett’s post hoc test.

Results

Treatment of HPB242 (5 mg/kg for 1 month) significantly attenuated cognitive impairments in Tg2576 transgenic mice. HPB242 also prevented amyloidogenesis in Tg2576 transgenic mice brains. This can be evidenced by Aβ accumulation, BACE1, APP and C99 expression and β-secretase activity. In addition, HPB242 suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes and microglial cells. Furthermore, activation of nuclear factor-kappaB (NF-κB) and signal transducer and activator of transcription 1/3 (STAT1/3) in the brain was potently inhibited by HPB242.

Conclusions

Thus, these results suggest that HPB242 might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.
Literature
1.
Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Prusiner SB: Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease. Proc Natl Acad Sci USA 2011, 108:2528–2533.CrossRefPubMedPubMedCentral
2.
Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH: Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci 2012, 32:9773–9784.CrossRefPubMed
3.
So PP, Zeldich E, Seyb KI, Huang MM, Concannon JB, King GD, Chen CD, Cuny GD, Glicksman MA, Abraham CR: Lowering of amyloid beta peptide production with a small molecule inhibitor of amyloid-beta precursor protein dimerization. Am J Neurodegener Dis 2012, 1:75–87.PubMedPubMedCentral
4.
Tuppo EE, Arias HR: The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005, 37:289–305.CrossRefPubMed
5.
Orellana DI, Quintanilla RA, Maccioni RB: Neuroprotective effect of TNFalpha against the beta-amyloid neurotoxicity mediated by CDK5 kinase. Biochim Biophys Acta 2007, 1773:254–263.CrossRefPubMed
6.
Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, Lee K, Cho WG, Jung JK, Han SB, Han JY, Nam SY, Yun YW, Jeong JH, Oh KW, Hong JT: Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflammation 2012, 9:35.PubMedPubMedCentral
7.
Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, Mook-Jung I: IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia 2007, 55:253–262.CrossRefPubMed
8.
Heneka MT, O'Banion MK: Inflammatory processes in Alzheimer's disease. J Neuroimmunol 2007, 184:69–91.CrossRefPubMed
9.
Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT: Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 2003, 23:9796–9804.PubMed
10.
Lee YJ, Choi DY, Choi IS, Han JY, Jeong HS, Han SB, Oh KW, Hong JT: Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-beta generation and inflammatory reactions via inhibition of NF-kappaB and STAT3 activation in cultured astrocytes and microglial BV-2 cells. J Neuroinflammation 2011, 8:132.CrossRefPubMedPubMedCentral
11.
Finnie JW, Blumbergs PC, Williamson MM: Alzheimer type II astrocytes in the brains of pigs with salt poisoning (water deprivation/intoxication). Aust Vet J 2010, 88:405–407.CrossRefPubMed
12.
Lin GH, Lee YJ, Choi DY, Han SB, Jung JK, Hwang BY, Moon DC, Kim Y, Lee MK, Oh KW, Jeong HS, Leem JY, Shin HK, Lee JH, Hong JT: Anti-amyloidogenic effect of thiacremonone through anti-inflamation in vitro and in vivo models. J Alzheimers Dis 2012, 29:659–676.PubMed
13.
Korolainen MA, Auriola S, Nyman TA, Alafuzoff I, Pirttila T: Proteomic analysis of glial fibrillary acidic protein in Alzheimer's disease and aging brain. Neurobiol Dis 2005, 20:858–870.CrossRefPubMed
14.
Cai Y, Zhang XM, Macklin LN, Cai H, Luo XG, Oddo S, Laferla FM, Struble RG, Rose GM, Patrylo PR, Yan XX: BACE1 elevation is involved in amyloid plaque development in the triple transgenic model of Alzheimer's disease: differential Aβ antibody labeling of early-onset axon terminal pathology. Neurotox Res 2012, 21:160–174.CrossRefPubMed
15.
Jekabsone A, Mander PK, Tickler A, Sharpe M, Brown GC: Fibrillar beta-amyloid peptide Abeta1–40 activates microglial proliferation via stimulating TNF-alpha release and H2O2 derived from NADPH oxidase: a cell culture study. J Neuroinflammation 2006, 3:24.CrossRefPubMedPubMedCentral
16.
Strohmeyer R, Kovelowski CJ, Mastroeni D, Leonard B, Grover A, Rogers J: Microglial responses to amyloid beta peptide opsonization and indomethacin treatment. J Neuroinflammation 2005, 2:18.CrossRefPubMedPubMedCentral
17.
Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, Perry G, Shimohama S: Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. FASEB J 2002, 16:601–603.PubMed
18.
Jin M, Suh SJ, Yang JH, Lu Y, Kim SJ, Kwon S, Jo TH, Kim JW, Park YI, Ahn GW, Lee CK, Kim CH, Son JK, Son KH, Chang HW: Anti-inflammatory activity of bark of Dioscorea batatas DECNE through the inhibition of iNOS and COX-2 expressions in RAW264.7 cells via NF-kappaB and ERK1/2 inactivation. Food Chem Toxicol 2010, 48:3073–3079.CrossRefPubMed
19.
Valerio A, Boroni F, Benarese M, Sarnico I, Ghisi V, Bresciani LG, Ferrario M, Borsani G, Spano P, Pizzi M: NF-kappaB pathway: a target for preventing beta-amyloid (Aβ)-induced neuronal damage and Aβ42 production. Eur J Neurosci 2006, 23:1711–1720.CrossRefPubMed
20.
Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Tong Y, Song W: Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol 2011, 15:77–90.CrossRefPubMed
21.
Na CH, Jeon SH, Zhang G, Olson GL, Chae CB: Inhibition of amyloid beta-peptide production by blockage of beta-secretase cleavage site of amyloid precursor protein. J Neurochem 2007, 101:1583–1595.CrossRefPubMed
22.
Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, Oh KW, Hong JT: Green tea (−)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice. J Nutr 2009, 139:1987–1993.CrossRefPubMed
23.
Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, Krishnamurthy P, Liu L, Planel E, Lau LF, Lahiri DK, Duff K: Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron 2008, 57:680–690.CrossRefPubMedPubMedCentral
24.
Hagihara K, Nishikawa T, Sugamata Y, Song J, Isobe T, Taga T, Yoshizaki K: Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression. Genes Cells 2005, 10:1051–1063.CrossRefPubMed
25.
Capiralla H, Vingtdeux V, Zhao H, Sankowski R, Al-Abed Y, Davies P, Marambaud P: Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-kappaB/STAT signaling cascade. J Neurochem 2012, 120:461–472.CrossRefPubMed
26.
Kile BT, Alexander WS: The suppressors of cytokine signalling (SOCS). Cell Mol Life Sci 2001, 58:1627–1635.CrossRefPubMed
27.
Cho HJ, Jin SM, Son SM, Kim YW, Hwang JY, Hong HS, Mook-Jung I: Constitutive JAK2/STAT1 activation regulates endogenous BACE1 expression in neurons. Biochem Biophys Res Commun 2009, 386:175–180.CrossRefPubMed
28.
Wan J, Fu AK, Ip FC, Ng HK, Hugon J, Page G, Wang JH, Lai KO, Wu Z, Ip NY: Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease. J Neurosci 2010, 30:6873–6881.CrossRefPubMed
29.
Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, Aiso S: Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry 2009, 14:206–222.CrossRefPubMed
30.
Kundinger MM, Zabala-Diaz IB, Chalova VI, Ricke SC: Effects of Maillard reaction products on hilA expression in Salmonella typhimurium. J Food Sci 2008, 73:M32–35.CrossRefPubMed
31.
Morales FJ, Babbel MB: Antiradical efficiency of Maillard reaction mixtures in a hydrophilic media. J Agric Food Chem 2002, 50:2788–2792.CrossRefPubMed
32.
Yen GC, Tsai LC, Lii JD: Antimutagenic effect of Maillard browning products obtained from amino acids and sugars. Food Chem Toxicol 1992, 30:127–132.CrossRefPubMed
33.
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996, 274:99–102.CrossRefPubMed
34.
Hwang IG, Kim HY, Woo KS, Hong JT, Hwang BY, Jung JK, Lee J, Jeong HS: Isolation and characterisation of an α-glucosidase inhibitory substance from fructose–tyrosine Maillard reaction products. Food Chem 2011, 127:122–126.CrossRef
35.
Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984, 11:47–60.CrossRefPubMed
36.
Veerhuis R: Histological and direct evidence for the role of complement in the neuroinflammation of AD. Curr Alzheimer Res 2011, 8:34–58.CrossRefPubMed
37.
McGeer EG, McGeer PL: Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 2003, 27:741–749.CrossRefPubMed
38.
Eikelenboom P, Bate C, Van Gool WA, Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams A: Neuroinflammation in Alzheimer's disease and prion disease. Glia 2002, 40:232–239.CrossRefPubMed
39.
Ruan L, Kang Z, Pei G, Le Y: Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer's disease. Curr Alzheimer Res 2009, 6:531–540.CrossRefPubMed
40.
Puli L, Pomeshchik Y, Olas K, Malm T, Koistinaho J, Tanila H: Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer's disease. J Neuroinflammation 2012, 9:105.CrossRefPubMedPubMedCentral
41.
Lee YJ, Choi DY, Han SB, Kim YH, Kim KH, Hwang BY, Kang JK, Lee BJ, Oh KW, Hong JT: Inhibitory effect of ethanol extract of Magnolia officinalis on memory impairment and amyloidogenesis in a transgenic mouse model of Alzheimer's disease via regulating beta-secretase activity. Phytother Res 2012, 10:4643.
42.
Choi DY, Lee JW, Peng J, Lee YJ, Han JY, Lee YH, Choi IS, Han SB, Jung JK, Lee WS, Lee SH, Kwon BM, Oh KW, Hong JT: Obovatol improves cognitive functions in animal models for Alzheimer's disease. J Neurochem 2012, 120:1048–1059.CrossRefPubMed
43.
Lee YK, Choi IS, Ban JO, Lee HJ, Lee US, Han SB, Jung JK, Kim YH, Kim KH, Oh KW, Hong JT: 4-O-methylhonokiol attenuated beta-amyloid-induced memory impairment through reduction of oxidative damages via inactivation of p38 MAP kinase. J Nutr Biochem 2011, 22:476–486.CrossRefPubMed
44.
45.
46.
Vassar R: BACE1: the beta-secretase enzyme in Alzheimer's disease. J Mol Neurosci 2004, 23:105–114.CrossRefPubMed
47.
Lee YJ, Choi DY, Yun YP, Han SB, Kim HM, Lee K, Choi SH, Yang MP, Jeon HS, Jeong JH, Oh KW, Hong JT: Ethanol extract of magnolia officinalis prevents lipopolysaccharide-induced memory deficiency via its antineuroinflammatory and antiamyloidogenic effects. Phytother Res 2012, 10:4740.
48.
von Bernhardi R, Ramirez G: Microglia-astrocyte interaction in Alzheimer's disease: friends or foes for the nervous system? Biol Res 2001, 34:123–128.CrossRefPubMed
49.
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F: Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2005, 2:22.CrossRefPubMedPubMedCentral
50.
Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T: Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 2007, 170:680–692.CrossRefPubMedPubMedCentral
51.
Bourne KZ, Ferrari DC, Lange-Dohna C, Rossner S, Wood TG, Perez-Polo JR: Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J Neurosci Res 2007, 85:1194–1204.CrossRefPubMed
52.
Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK: Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J 2004, 18:1034–1036.PubMed
53.
Chami L, Buggia-Prevot V, Duplan E, Delprete D, Chami M, Peyron JF, Checler F: Nuclear factor-kappaB Regulates betaAPP and beta- and gamma-secretases differently at physiological and supraphysiological abeta concentrations. J Biol Chem 2012, 287:24573–24584.CrossRefPubMedPubMedCentral
54.
Echeverria V, Burgess S, Gamble-George J, Zeitlin R, Lin X, Cao C, Arendash GW: Sorafenib inhibits nuclear factor kappa B, decreases inducible nitric oxide synthase and cyclooxygenase-2 expression, and restores working memory in APPswe mice. Neuroscience 2009, 162:1220–1231.CrossRefPubMed
55.
Kim TI, Lee YK, Park SG, Choi IS, Ban JO, Park HK, Nam SY, Yun YW, Han SB, Oh KW, Hong JT: l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med 2009, 47:1601–1610.CrossRefPubMed
56.
Pan XD, Chen XC, Zhu YG, Chen LM, Zhang J, Huang TW, Ye QY, Huang HP: Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-kappaB and JNK signaling. Glia 2009, 57:1227–1238.CrossRefPubMed
57.
Kitamura Y, Shimohama S, Ota T, Matsuoka Y, Nomura Y, Taniguchi T: Alteration of transcription factors NF-kappaB and STAT1 in Alzheimer's disease brains. Neurosci Lett 1997, 237:17–20.CrossRefPubMed
58.
Fagerlund R, Melen K, Cao X, Julkunen I: NF-kappaB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules. Cell Signal 2008, 20:1442–1451.CrossRefPubMed
Metadata
Title
Anti-inflammatory and anti-amyloidogenic effects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’s disease mice model
Authors
Peng Jin
Jin-A Kim
Dong-Young Choi
Young-Jung Lee
Heon Sang Jung
Jin Tae Hong
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2013
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-10-2

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