The contribution of activated astrocytes to Aβ production: Implications for Alzheimer's disease pathogenesis

Journal of Neuroinflammation

Robert Vassar¹  Tracy O'Connor¹  Jie Zhao¹ 

[1] Department of Cell & Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA

关键词: TNF-α;    oligomer;    Neuroinflammation;    IFN-γ;    Cytokine;    β-secretase;    BACE1;    Astrocyte;    APP;    Aβ;   

Others  :  1213031
DOI  :  10.1186/1742-2094-8-150

 received in 2011-08-26, accepted in 2011-11-02,  发布年份 2011

【 摘 要 】

Background

β-Amyloid (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Neurons are major sources of Aβ in the brain. However, astrocytes outnumber neurons by at least five-fold. Thus, even a small level of astrocytic Aβ production could make a significant contribution to Aβ burden in AD. Moreover, activated astrocytes may increase Aβ generation. β-Site APP cleaving enzyme 1 (BACE1) cleavage of amyloid precursor protein (APP) initiates Aβ production. Here, we explored whether pro-inflammatory cytokines or Aβ42 would increase astrocytic levels of BACE1, APP, and β-secretase processing, implying a feed-forward mechanism of astrocytic Aβ production.

Methods

Mouse primary astrocytes were treated with combinations of LPS, TNF-α, IFN-γ, and IL-1β and analyzed by immunoblot and ELISA for endogenous BACE1, APP, and secreted Aβ40 levels. Inhibition of JAK and iNOS signaling in TNF-α+IFN-γ-stimulated astrocytes was also analyzed. In addition, C57BL/6J or Tg2576 mouse astrocytes were treated with oligomeric or fibrillar Aβ42 and analyzed by immunoblot for levels of BACE1, APP, and APPsβsw. Astrocytic BACE1 and APP mRNA levels were measured by TaqMan RT-PCR.

Results

TNF-α+IFN-γ stimulation significantly increased levels of astrocytic BACE1, APP, and secreted Aβ40. BACE1 and APP elevations were post-transcriptional at early time-points, but became transcriptional with longer TNF-α+IFN-γ treatment. Despite a ~4-fold increase in astrocytic BACE1 protein level following TNF-α+IFN-γ stimulation, BACE1 mRNA level was significantly decreased suggesting a post-transcriptional mechanism. Inhibition of iNOS and JAK did not reduce TNF-α+IFN-γ-stimulated elevation of astrocytic BACE1, APP, and Aβ40, except that JAK inhibition blocked the APP increase. Finally, oligomeric and fibrillar Aβ42 dramatically increased levels of astrocytic BACE1, APP, and APPsβsw through transcriptional mechanisms, at least in part.

Conclusions

Cytokines including TNF-α+IFN-γ increase levels of endogenous BACE1, APP, and Aβ and stimulate amyloidogenic APP processing in astrocytes. Oligomeric and fibrillar Aβ42 also increase levels of astrocytic BACE1, APP, and β-secretase processing. Together, our results suggest a cytokine- and Aβ42-driven feed-forward mechanism that promotes astrocytic Aβ production. Given that astrocytes greatly outnumber neurons, activated astrocytes may represent significant sources of Aβ during neuroinflammation in AD.

【 授权许可】

   
2011 Zhao et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Holtzman DM, Morris JC, Goate AM: Alzheimer's disease: the challenge of the second century. Sci Transl Med 2011, 3:77sr1.
• [2]De Strooper B: Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 2010, 90:465-94.
• [3]Heneka MT, O'Banion MK, Terwel D, Kummer MP: Neuroinflammatory processes in Alzheimer's disease. J Neural Transm 2010, 117:919-47.
• [4]Mrak RE, Griffin WS: Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 2005, 26:349-54.
• [5]Sastre M, Walter J, Gentleman SM: Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 2008, 5:25. BioMed Central Full Text
• [6]Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C: Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 1989, 86:7611-7615.
• [7]Griffin WS, Sheng JG, Roberts GW, Mrak RE: Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol 1995, 54:276-281.
• [8]Dandrea MR, Reiser PA, Gumula NA, Hertzog BM, Andrade-Gordon P: Application of triple immunohistochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer's disease. Biotech Histochem 2001, 76:97-106.
• [9]Maat-Schieman ML, Rozemuller AJ, van Duinen SG, Haan J, Eikelenboom P, Roos RA: Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical study. J Neuropathol Exp Neurol 1994, 53:483-491.
• [10]Van Eldik LJ, Griffin WS: S100 beta expression in Alzheimer's disease: relation to neuropathology in brain regions. Biochim Biophys Acta 1994, 1223:398-403.
• [11]Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, Brunden KR: Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging 1999, 20:581-9.
• [12]Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O'Banion MK, Tenner AJ, Lemere CA, Duff K: Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am J Pathol 2001, 158:1345-54.
• [13]Bornemann KD, Wiederhold KH, Pauli C, Ermini F, Stalder M, Schnell L, Sommer B, Jucker M, Staufenbiel M: Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am J Pathol 2001, 158:63-73.
• [14]Dudal S, Krzywkowski P, Paquette J, Morissette C, Lacombe D, Tremblay P, Gervais F: Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging 2004, 25:861-71.
• [15]Gärtner U, Brückner MK, Krug S, Schmetsdorf S, Staufenbiel M, Arendt T: Amyloid deposition in APP23 mice is associated with the expression of cyclins in astrocytes but not in neurons. Acta Neuropathol 2003, 106:535-44.
• [16]Terai K, Iwai A, Kawabata S, Sasamata M, Miyata K, Yamaguchi T: Apolipoprotein E deposition and astrogliosis are associated with maturation of beta-amyloid plaques in betaAPPswe transgenic mouse: Implications for the pathogenesis of Alzheimer's disease. Brain Res 2001, 900:48-56.
• [17]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, et al.: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421.
• [18]Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE: Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998, 8:65-72.
• [19]Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG: Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener 2009, 4:47. BioMed Central Full Text
• [20]McGeer PL, McGeer EG: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995, 21:195-218.
• [21]Zhao J, Paganini L, Mucke L, Gordon M, Refolo L, Carman M, Sinha S, Oltersdorf T, Lieberburg I, McConlogue L: Beta-secretase processing of the beta-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes. J Biol Chem 1996, 271:31407-11.
• [22]Calhoun ME, Burgermeister P, Phinney AL, Stalder M, Tolnay M, Wiederhold KH, Abramowski D, Sturchler-Pierrat C, Sommer B, Staufenbiel M, Jucker M: Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 1999, 96:14088-93.
• [23]Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286:735-41.
• [24]Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999, 402:533-7.
• [25]Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999, 402:537-40.
• [26]Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999, 14:419-27.
• [27]Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J: Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 2000, 97:1456-60.
• [28]Laird FM, Cai H, Savonenko AV, Farah MH, He K, Melnikova T, Wen H, Chiang HC, Xu G, Koliatsos VE, Borchelt DR, Price DL, Lee HK, Wong PC: BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005, 25:11693-709.
• [29]Sofroniew MV, Vinters HV: Astrocytes: biology and pathology. Acta Neuropathol 2010, 119:7-35.
• [30]Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science. 4th edition. New York: McGraw-Hill Medical Press; 2000.
• [31]Brugg B, Dubreuil YL, Huber G, Wollman EE, Delhaye-Bouchaud N, Mariani J: Inflammatory processes induce beta-amyloid precursor protein changes in mouse brain. Proc Natl Acad Sci USA 1995, 92:3032-5.
• [32]Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE: Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 2003, 14:133-45.
• [33]Blasko I, Marx F, Steiner E, Hartmann T, Grubeck-Loebenstein B: TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J 1999, 13:63-8.
• [34]Rogers JT, Leiter LM, McPhee J, Cahill CM, Zhan SS, Potter H, Nilsson LN: Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. J Biol Chem 1999, 274:6421-31.
• [35]Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B: Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1-40 and Abeta1-42 by human astrocytes. Neurobiol Dis 2000, 7:682-9.
• [36]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, 23:9796-804.
• [37]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.
• [38]Hong HS, Hwang EM, Sim HJ, Cho HJ, Boo JH, Oh SS, Kim SU, Mook-Jung I: Interferon gamma stimulates beta-secretase expression and sAPPbeta production in astrocytes. Biochem Biophys Res Commun 2003, 307:922-7.
• [39]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, 55:253-62.
• [40]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, 170:680-92.
• [41]He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y: Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol 2007, 178:829-41.
• [42]Hu J, Akama KT, Krafft GA, Chromy BA, Van Eldik LJ: Amyloid-beta peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release. Brain Res 1998, 785:195-206.
• [43]White JA, Manelli AM, Holmberg KH, Van Eldik LJ, Ladu MJ: Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis 2005, 18:459-65.
• [44]Akama KT, Van Eldik LJ: Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J Biol Chem 2000, 275:7918-24.
• [45]Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ: Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging 2004, 25:1283-92.
• [46]Nimmrich V, Ebert U: Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci 2009, 20:1-12.
• [47]Hu J, Castets F, Guevara JL, Van Eldik LJ: S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biol Chem 1996, 271:2543-7.
• [48]Stine WB, Jungbauer L, Yu C, LaDu MJ: Preparing synthetic Aβ in different aggregation states. Methods Mol Biol 2011, 670:13-32.
• [49]Velliquette RA, O'Connor T, Vassar R: Energy inhibition elevates beta-secretase levels and activity and is potentially amyloidogenic in APP transgenic mice: possible early events in Alzheimer's disease pathogenesis. J Neurosci 2005, 25:10874-83.
• [50]Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R: Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001, 4:231-2.
• [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, 85:1194-204.
• [52]Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ: Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 1992, 360:672-4.
• [53]Tachida Y, Nakagawa K, Saito T, Saido TC, Honda T, Saito Y, Murayama S, Endo T, Sakaguchi G, Kato A, Kitazume S, Hashimoto Y: Interleukin-1 beta up-regulates TACE to enhance alpha-cleavage of APP in neurons: resulting decrease in Abeta production. J Neurochem 2008, 104:1387-93.
• [54]Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'Banion MK: Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 2007, 117:1595-604.
• [55]Rogers JT, Leiter LM, McPhee J, Cahill CM, Zhan SS, Potter H, Nilsson LN: Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences. J Biol Chem 1999, 274:6421-31.
• [56]Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 2007, 54:721-37.
• [57]O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hébert SS, De Strooper B, Haass C, Bennett DA, Vassar R: Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 2008, 60:988-1009.
• [58]Wu Y, Zhou BP: TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer 2010, 102:639-44.
• [59]Saha B, Jyothi Prasanna S, Chandrasekar B, Nandi D: Gene modulation and immunoregulatory roles of interferon gamma. Cytokine 2010, 50:1-14.
• [60]Bettegazzi B, Mihailovich M, Di Cesare A, Consonni A, Macco R, Pelizzoni I, Codazzi F, Grohovaz F, Zacchetti D: β-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression. Eur J Neurosci 2011, 33:236-43.
• [61]Barger SW, Harmon AD: Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 1997, 388:878-81.
• [62]Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ: Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010, 330:1774.
• [63]Castellano JM, Kim J, Stewart FR, Jiang H, Demattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM: Human apoE Isoforms Differentially Regulate Brain Amyloid-beta Peptide Clearance. Sci Transl Med 2011, 3:89ra57.