BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease

Molecular Neurodegeneration

Frédéric Checler¹  Linda Chami¹ 

[1] LABEX (Laboratory of Excellence), 660 route des Lucioles, Sophia Antipolis, 06560, Valbonne, France

关键词: Calcium;    Oxidative stress;    Inflammation;    BACE1;    Alzheimer’s disease;   

Others  :  863762
DOI  :  10.1186/1750-1326-7-52

 received in 2012-07-13, accepted in 2012-10-03,  发布年份 2012

【 摘 要 】

Alzheimer’s disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of “full length” Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.

【 授权许可】

   
2012 Chami and Checler; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Querfurth HW, LaFerla FM: Alzheimer's disease. N Engl J Med 2010, 362:329-344.
• [2]Kern A, Behl C: The unsolved relationship of brain aging and late-onset Alzheimer disease. Biochim Biophys Acta 2009, 1790:1124-1132.
• [3]Lambert JC, Amouyel P: Genetics of Alzheimer's disease: new evidences for an old hypothesis? Curr Opin Genet Dev 2011, 21:295-301.
• [4]Rossner S, Apelt J, Schliebs R, Perez-Polo JR, Bigl V: Neuronal and glial beta-secretase (BACE) protein expression in transgenic Tg2576 mice with amyloid plaque pathology. J Neurosci Res 2001, 64:437-446.
• [5]Checler F: Processing of the beta-amyloid precursor protein and its regulation in Alzheimer's disease. J Neurochem 1995, 65:1431-1444.
• [6]Suh YH, Checler F: Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev 2002, 54:469-525.
• [7]St George-Hyslop PH: Molecular genetics of Alzheimer's disease. Biol Psychiatry 2000, 47:183-199.
• [8]Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, et al.: A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012, 488:96-9.
• [9]Sevalle J, Amoyel A, Robert P, Fournie-Zaluski MC, Roques B, Checler F: Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide. J Neurochem 2009, 109:248-256.
• [10]Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, et al.: Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat Med 2008, 14:1106-1111.
• [11]Di Carlo M: Beta amyloid peptide: from different aggregation forms to the activation of different biochemical pathways. Eur Biophys J 2010, 39:877-888.
• [12]Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002, 416:535-539.
• [13]Wang DS, Dickson DW, Malter JS: beta-Amyloid degradation and Alzheimer's disease. J Biomed Biotechnol 2006, 2006:58406.
• [14]Yasojima K, Akiyama H, McGeer EG, McGeer PL: Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of beta-amyloid peptide. Neurosci Lett 2001, 297:97-100.
• [15]Wang S, Wang R, Chen L, Bennett DA, Dickson DW, Wang DS: Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J Neurochem 2010, 115:47-57.
• [16]Hunter S, Brayne C: Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems. Alzheimers Res Ther 2012, 4:10.
• [17]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 (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci 2006, 23:1711-1720.
• [18]Maloney B, Lahiri DK: The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif. Gene 2011, 488:1-12.
• [19]Bailey JA, Maloney B, Ge YW, Lahiri DK: Functional activity of the novel Alzheimer's amyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis. Gene 2011, 488:13-22.
• [20]Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, et al.: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286:735-741.
• [21]Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, et al.: Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999, 402:537-540.
• [22]Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, et al.: Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999, 402:533-537.
• [23]Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, et al.: Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999, 14:419-427.
• [24]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, 97:1456-1460.
• [25]Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, et al.: BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet 2001, 10:1317-1324.
• [26]Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, et al.: Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001, 4:231-232.
• [27]Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC: BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001, 4:233-234.
• [28]Vassar R: The beta-secretase, BACE: a prime drug target for Alzheimer's disease. J Mol Neurosci 2001, 17:157-170.
• [29]Cole SL, Vassar R: The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener 2007, 2:22.
• [30]Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R: Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006, 9:1520-1525.
• [31]Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C: Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006, 314:664-666.
• [32]Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC: Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA 2008, 105:5585-5590.
• [33]Hu X, Zhou X, He W, Yang J, Xiong W, Wong P, Wilson CG, Yan R: BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 2010, 30:8819-8829.
• [34]Devi L, Alldred MJ, Ginsberg SD, Ohno M: Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease. Mol Brain 2010, 3:34.
• [35]Wang Y, Li M, Tang J, Song M, Xu X, Xiong J, Li J, Bai Y: Glucocorticoids facilitate astrocytic amyloid-beta peptide deposition by increasing the expression of APP and BACE1 and decreasing the expression of amyloid-beta-degrading proteases. Endocrinology 2011, 152:2704-2715.
• [36]Vassar R, Kovacs DM, Yan R, Wong PC: The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 2009, 29:12787-12794.
• [37]Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W: Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol 2004, 24:865-874.
• [38]Nowak K, Lange-Dohna C, Zeitschel U, Gunther A, Luscher B, Robitzki A, Perez-Polo R, Rossner S: The transcription factor Yin Yang 1 is an activator of BACE1 expression. J Neurochem 2006, 96:1696-1707.
• [39]Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, et al.: Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA 2006, 103:443-448.
• [40]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.
• [41]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, 1-14.
• [42]Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW: Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem 2007, 282:10873-10880.
• [43]Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marie I, Maurin T, Wang L, Figueroa H, Herman M, et al.: Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron 2008, 57:680-690.
• [44]Fukumoto H, Rosene DL, Moss MB, Raju S, Hyman BT, Irizarry MC: Beta-secretase activity increases with aging in human, monkey, and mouse brain. Am J Pathol 2004, 164:719-725.
• [45]Fukumoto H, Cheung BS, Hyman BT, Irizarry MC: Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002, 59:1381-1389.
• [46]Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O'Connor T, Logan S, Maus E, Citron M, Berry R, et al.: Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci 2007, 27:3639-3649.
• [47]Rossner S, Sastre M, Bourne K, Lichtenthaler SF: Transcriptional and translational regulation of BACE1 expression–implications for Alzheimer's disease. Prog Neurobiol 2006, 79:95-111.
• [48]Stockley JH, O'Neill C: Understanding BACE1: essential protease for amyloid-beta production in Alzheimer's disease. Cell Mol Life Sci 2008, 65:3265-3289.
• [49]Wang JF, Lu R, Wang YZ: Regulation of beta cleavage of amyloid precursor protein. Neurosci Bull 2010, 26:417-427.
• [50]Tamagno E, Bardini P, Guglielmotto M, Danni O, Tabaton M: The various aggregation states of beta-amyloid 1–42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression. Free Radic Biol Med 2006, 41:202-212.
• [51]Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, et al.: Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem 2008, 104:683-695.
• [52]Buggia-Prevot V, Sevalle J, Rossner S, Checler F: NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. J Biol Chem 2008, 283:10037-10047.
• [53]Sadleir KR, Vassar R: Cdk5 protein inhibition and Abeta42 increase BACE1 protein level in primary neurons by a post-transcriptional mechanism: implications of CDK5 as a therapeutic target for Alzheimer disease. J Biol Chem 2012, 287:7224-7235.
• [54]Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J: Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007, 39:44-84.
• [55]Harman D: Free radicals in aging. Mol Cell Biochem 1988, 84:155-161.
• [56]Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N: Oxidative damage in Alzheimer's. Nature 1996, 382:120-121.
• [57]Behl C, Moosmann B: Antioxidant neuroprotection in Alzheimer's disease as preventive and therapeutic approach. Free Radic Biol Med 2002, 33:182-191.
• [58]Guglielmotto M, Giliberto L, Tamagno E, Tabaton M: Oxidative stress mediates the pathogenic effect of different Alzheimer's disease risk factors. Front Aging Neurosci 2010, 2:3.
• [59]Sultana R, Butterfield DA: Role of Oxidative Stress in the Progression of Alzheimer's Disease. J Alzheimers Dis 2009.
• [60]Butterfield DA, Abdul HM, Opii W, Newman SF, Joshi G, Ansari MA, Sultana R: Pin1 in Alzheimer's disease. J Neurochem 2006, 98:1697-1706.
• [61]Castellani RJ, Lee HG, Perry G, Smith MA: Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tau. Am J Alzheimers Dis Other Demen 2006, 21:126-130.
• [62]Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, et al.: The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 1999, 38:7609-7616.
• [63]Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, et al.: Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 1999, 274:37111-37116.
• [64]Kim HC, Yamada K, Nitta A, Olariu A, Tran MH, Mizuno M, Nakajima A, Nagai T, Kamei H, Jhoo WK, et al.: Immunocytochemical evidence that amyloid beta (1–42) impairs endogenous antioxidant systems in vivo. Neuroscience 2003, 119:399-419.
• [65]Borghi R, Patriarca S, Traverso N, Piccini A, Storace D, Garuti A, Gabriella C, Patrizio O, Massimo T: The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease. Neurobiol Aging 2007, 28:1009-1014.
• [66]Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W: Oxidative stress potentiates BACE1 gene expression and Abeta generation. J Neural Transm 2005, 112:455-469.
• [67]Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M: Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 2002, 10:279-288.
• [68]Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, Zaccheo D, Odetti P, Strocchi P, Marinari UM, et al.: Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 2000, 268:642-646.
• [69]Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, et al.: Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem 2005, 92:628-636.
• [70]Mehan S, Meena H, Sharma D, Sankhla R: JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalities. J Mol Neurosci 2011, 43:376-390.
• [71]Yao M, Nguyen TV, Pike CJ: Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J Neurosci 2005, 25:1149-1158.
• [72]Guglielmotto M, Monteleone D, Giliberto L, Fornaro M, Borghi R, Tamagno E, Tabaton M: Amyloid-beta activates the expression of BACE1 through the JNK pathway. J Alzheimers Dis 2011, 27:871-883.
• [73]Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA: Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem 2001, 76:435-441.
• [74]Tamagno E, Parola M, Guglielmotto M, Santoro G, Bardini P, Marra L, Tabaton M, Danni O: Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis. Free Radic Biol Med 2003, 35:45-58.
• [75]Sastre M, Klockgether T, Heneka MT: Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci 2006, 24:167-176.
• [76]Tuppo EE, Arias HR: The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005, 37:289-305.
• [77]Lynch MA: Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci 2010, 1:6.
• [78]Eikelenboom P, Veerhuis R: The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol Aging 1996, 17:673-680.
• [79]Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al.: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421.
• [80]Krause DL, Muller N: Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimer's disease. Int J Alzheimers Dis 2010.
• [81]Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease–a double-edged sword. Neuron 2002, 35:419-432.
• [82]Munch G, Gasic-Milenkovic J, Dukic-Stefanovic S, Kuhla B, Heinrich K, Riederer P, Huttunen HJ, Founds H, Sajithlal G: Microglial activation induces cell death, inhibits neurite outgrowth and causes neurite retraction of differentiated neuroblastoma cells. Exp Brain Res 2003, 150:1-8.
• [83]Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F: Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995, 374:647-650.
• [84]Johnstone M, Gearing AJ, Miller KM: A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 1999, 93:182-193.
• [85]Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE: A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 2003, 23:2665-2674.
• [86]Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, et al.: RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 1996, 382:685-691.
• [87]Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, et al.: Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 1992, 89:10016-10020.
• [88]Mercurio F, Manning AM: NF-kappaB as a primary regulator of the stress response. Oncogene 1999, 18:6163-6171.
• [89]Schreck R, Rieber P, Baeuerle PA: Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991, 10:2247-2258.
• [90]Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP: Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats. Stroke 1997, 28:1073-1080. discussion 1080–1071
• [91]Yang K, Mu XS, Hayes RL: Increased cortical nuclear factor-kappa B (NF-kappa B) DNA binding activity after traumatic brain injury in rats. Neurosci Lett 1995, 197:101-104.
• [92]Lawrence T: The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 2009, 1:a001651.
• [93]Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C: Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci USA 1997, 94:2642-2647.
• [94]Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C: Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA 1999, 96:9409-9414.
• [95]Terai K, Matsuo A, McGeer PL: Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res 1996, 735:159-168.
• [96]Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP: Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 1995, 92:9328-9332.
• [97]Huang X, Chen Y, Zhang H, Ma Q, Zhang YW, Xu H: Salubrinal attenuates beta-amyloid-induced neuronal death and microglial activation by inhibition of the NF-kappaB pathway. Neurobiol Aging 2011.
• [98]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, 14:133-145.
• [99]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.
• [100]Chami L, Buggia-Prevot V, Duplan E, Delprete D, Chami M, Peyron JF, Checler F: Nuclear factor-kappa B regulates betaAPP and beta- and gamma-secretases differently at physiological and supraphysiological Abeta concentrations. J Biol Chem 2012, 287:24573-24584.
• [101]Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, Trojanowski JQ, Lee VM, Pratico D: Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease. Am J Pathol 2004, 165:2197-2206.
• [102]Paris D, Ganey NJ, Laporte V, Patel NS, Beaulieu-Abdelahad D, Bachmeier C, March A, Ait-Ghezala G, Mullan MJ: Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 2010, 7:17.
• [103]Choi DY, Lee JW, Lin G, Lee YK, Lee YH, Choi IS, Han SB, Jung JK, Kim YH, Kim KH, et al.: Obovatol attenuates LPS-induced memory impairments in mice via inhibition of NF-kappaB signaling pathway. Neurochem Int 2011.
• [104]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, 178:829-841.
• [105]Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, et al.: AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiol Aging 2010, 33(196 e):113-127.
• [106]Heneka MT, Landreth GE: PPARs in the brain. Biochim Biophys Acta 2007, 1771:1031-1045.
• [107]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.
• [108]Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O'Banion K, Klockgether T, Van Leuven F, Landreth GE: Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005, 128:1442-1453.
• [109]D'Abramo C, Massone S, Zingg JM, Pizzuti A, Marambaud P, Dalla Piccola B, Azzi A, Marinari UM, Pronzato MA, Ricciarelli R: Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. Biochem J 2005, 391:693-698.
• [110]Gong B, Chen F, Pan Y, Arrieta-Cruz I, Yoshida Y, Haroutunian V, Pasinetti GM: SCF(Fbx2) -E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function. Aging Cell 2010, 9:1018-1031.
• [111]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.
• [112]Zhao J, O'Connor T, Vassar R: The contribution of activated astrocytes to Abeta production: Implications for Alzheimer's disease pathogenesis. J Neuroinflammation 2011, 8:150.
• [113]Amara FM, Junaid A, Clough RR, Liang B: TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization. Brain Res Mol Brain Res 1999, 71:42-49.
• [114]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, 274:6421-6431.
• [115]Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR: Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem 2005, 92:226-234.
• [116]Hartlage-Rubsamen M, Zeitschel U, Apelt J, Gartner U, Franke H, Stahl T, Gunther A, Schliebs R, Penkowa M, Bigl V, Rossner S: Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent. Glia 2003, 41:169-179.
• [117]Bettegazzi B, Mihailovich M, Di Cesare A, Consonni A, Macco R, Pelizzoni I, Codazzi F, Grohovaz F, Zacchetti D: beta-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression. Eur J Neurosci 2011.
• [118]Kihara T, Shimmyo Y, Akaike A, Niidome T, Sugimoto H: Abeta-induced BACE-1 cleaves N-terminal sequence of mPGES-2. Biochem Biophys Res Commun 2010, 393:728-733.
• [119]Berridge MJ, Bootman MD, Lipp P: Calcium–a life and death signal. Nature 1998, 395:645-648.
• [120]Small DH, Gasperini R, Vincent AJ, Hung AC, Foa L: The role of Abeta-induced calcium dysregulation in the pathogenesis of Alzheimer's disease. J Alzheimers Dis 2009, 16:225-233.
• [121]Berridge MJ: Calcium hypothesis of Alzheimer's disease. Pflugers Arch 2009, 459:441-449.
• [122]Bezprozvanny I, Mattson MP: Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci 2008, 31:454-463.
• [123]Gibson GE, Karuppagounder SS, Shi Q: Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease. Ann N Y Acad Sci 2008, 1147:221-232.
• [124]Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, et al.: A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 2008, 133:1149-1161.
• [125]Lambert JC, Sleegers K, Gonzalez-Perez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, et al.: The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. J Alzheimers Dis 2010, 22:247-255.
• [126]Alberdi E, Sanchez-Gomez MV, Cavaliere F, Perez-Samartin A, Zugaza JL, Trullas R, Domercq M, Matute C: Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 2010, 47:264-272.
• [127]Lin H, Bhatia R, Lal R: Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology. FASEB J 2001, 15:2433-2444.
• [128]Sepulveda FJ, Parodi J, Peoples RW, Opazo C, Aguayo LG: Synaptotoxicity of Alzheimer beta amyloid can be explained by its membrane perforating property. PLoS One 2010, 5:e11820.
• [129]Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP: Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 2000, 275:18195-18200.
• [130]Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK: Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron 2008, 58:871-883.
• [131]Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM: SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol 2008, 181:1107-1116.
• [132]Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, Moreno S, Paterlini-Bréchot P, Trebak M, Checler F, et al.: Ryanodine receptors blockade reduces Amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 2012, 32:11820-11834.
• [133]Cao X, Sudhof TC: A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 2001, 293:115-120.
• [134]Muller T, Meyer HE, Egensperger R, Marcus K: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer's disease. Prog Neurobiol 2008, 85:393-406.
• [135]Pardossi-Piquard R, Checler F: The physiology of the beta-amyloid precursor protein intracellular domain AICD. J Neurochem 2012, 120(Suppl 1):109-124.
• [136]Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Muller U, Saftig P, De Strooper B, et al.: A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci USA 2002, 99:4697-4702.
• [137]Hamid R, Kilger E, Willem M, Vassallo N, Kostka M, Bornhovd C, Reichert AS, Kretzschmar HA, Haass C, Herms J: Amyloid precursor protein intracellular domain modulates cellular calcium homeostasis and ATP content. J Neurochem 2007, 102:1264-1275.
• [138]Querfurth HW, Selkoe DJ: Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 1994, 33:4550-4561.
• [139]Pierrot N, Santos SF, Feyt C, Morel M, Brion JP, Octave JN: Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation. J Biol Chem 2006, 281:39907-39914.
• [140]Mattson MP: Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 1990, 4:105-117.
• [141]Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T, Maeda J, Ji B, Ono M, Staufenbiel M, Suhara T, Saido TC: Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J 2012, 26:1204-1217.
• [142]Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX: Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 2005, 280:37755-37762.
• [143]Liang B, Duan BY, Zhou XP, Gong JX, Luo ZG: Calpain activation promotes BACE1 expression, amyloid precursor protein processing, and amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Biol Chem 2010, 285:27737-27744.
• [144]Kusakawa G, Saito T, Onuki R, Ishiguro K, Kishimoto T, Hisanaga S: Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. J Biol Chem 2000, 275:17166-17172.
• [145]Cho HJ, Jin SM, Youn HD, Huh K, Mook-Jung I: Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell 2008, 7:137-147.
• [146]Hayley M, Perspicace S, Schulthess T, Seelig J: Calcium enhances the proteolytic activity of BACE1: An in vitro biophysical and biochemical characterization of the BACE1-calcium interaction. Biochim Biophys Acta 2009, 1788:1933-1938.
• [147]Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P: Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci USA 1994, 91:4489-4493.
• [148]Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH: Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 2000, 405:360-364.
• [149]Munch G, Thome J, Foley P, Schinzel R, Riederer P: Advanced glycation endproducts in ageing and Alzheimer's disease. Brain Res Brain Res Rev 1997, 23:134-143.
• [150]Li JJ, Surini M, Catsicas S, Kawashima E, Bouras C: Age-dependent accumulation of advanced glycosylation end products in human neurons. Neurobiol Aging 1995, 16:69-76.
• [151]Ramasamy R, Yan SF, Schmidt AM: Advanced glycation endproducts: from precursors to RAGE: round and round we go. Amino Acids 2010.
• [152]Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A: Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992, 267:14998-15004.
• [153]Yan SD, Yan SF, Chen X, Fu J, Chen M, Kuppusamy P, Smith MA, Perry G, Godman GC, Nawroth P, et al.: Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1995, 1:693-699.
• [154]Neumann A, Schinzel R, Palm D, Riederer P, Munch G: High molecular weight hyaluronic acid inhibits advanced glycation endproduct-induced NF-kappaB activation and cytokine expression. FEBS Lett 1999, 453:283-287.
• [155]Li J, Schmidt AM: Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 1997, 272:16498-16506.
• [156]Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G: Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 1994, 91:5710-5714.
• [157]Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A: Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA 1994, 91:4766-4770.
• [158]Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA, et al.: Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 1994, 91:7787-7791.
• [159]Dickson DW, Sinicropi S, Yen SH, Ko LW, Mattiace LA, Bucala R, Vlassara H: Glycation and microglial reaction in lesions of Alzheimer's disease. Neurobiol Aging 1996, 17:733-743.
• [160]Ledesma MD, Bonay P, Colaco C, Avila J: Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 1994, 269:21614-21619.
• [161]Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM: Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta 1997, 1360:17-29.
• [162]Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD: Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol 2001, 171:29-45.
• [163]Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, et al.: RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 2004, 23:4096-4105.
• [164]Ko SY, Lin YP, Lin YS, Chang SS: Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species. Free Radic Biol Med 2010, 49:474-480.
• [165]Cho HJ, Son SM, Jin SM, Hong HS, Shin DH, Kim SJ, Huh K, Mook-Jung I: RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB J 2009, 23:2639-2649.
• [166]Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA, Perry G, Danni O, et al.: AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiol Aging 2012, 33:196.e13-27.
• [167]Jellinger KA, Paulus W, Wrocklage C, Litvan I: Effects of closed traumatic brain injury and genetic factors on the development of Alzheimer's disease. Eur J Neurol 2001, 8:707-710.
• [168]Roberts GW, Gentleman SM, Lynch A, Graham DI: beta A4 amyloid protein deposition in brain after head trauma. Lancet 1991, 338:1422-1423.
• [169]Uryu K, Laurer H, McIntosh T, Pratico D, Martinez D, Leight S, Lee VM, Trojanowski JQ: Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 2002, 22:446-454.
• [170]Blasko I, Beer R, Bigl M, Apelt J, Franz G, Rudzki D, Ransmayr G, Kampfl A, Schliebs R: Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase (BACE-1). J Neural Transm 2004, 111:523-536.
• [171]Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH: Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 2004, 165:357-371.
• [172]Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, Faden AI, Rebeck GW, Burns MP: Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med 2009, 15:377-379.
• [173]Sanz O, Acarin L, Gonzalez B, Castellano B: NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain. J Neurosci Res 2002, 67:772-780.
• [174]von Arnim CA, Tangredi MM, Peltan ID, Lee BM, Irizarry MC, Kinoshita A, Hyman BT: Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy. J Cell Sci 2004, 117:5437-5445.
• [175]He X, Li F, Chang WP, Tang J: GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 2005, 280:11696-11703.
• [176]Wahle T, Prager K, Raffler N, Haass C, Famulok M, Walter J: GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network. Mol Cell Neurosci 2005, 29:453-461.
• [177]Walker KR, Kang EL, Whalen MJ, Shen Y, Tesco G: Depletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1. J Neurosci 2012, 32:10423-10437.
• [178]Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G: The role of vascular factors in late-onset sporadic Alzheimer's disease. Genetic and molecular aspects. Curr Alzheimer Res 2009, 6:224-237.
• [179]de la Torre JC: Pathophysiology of neuronal energy crisis in Alzheimer's disease. Neurodegener Dis 2008, 5:126-132.
• [180]Koistinaho M, Koistinaho J: Interactions between Alzheimer's disease and cerebral ischemia–focus on inflammation. Brain Res Brain Res Rev 2005, 48:240-250.
• [181]Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W: Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 2006, 103:18727-18732.
• [182]Guglielmotto M, Aragno M, Autelli R, Giliberto L, Novo E, Colombatto S, Danni O, Parola M, Smith MA, Perry G, et al.: The up-regulation of BACE1 mediated by hypoxia and ischemic injury: role of oxidative stress and HIF1alpha. J Neurochem 2009, 108:1045-1056.
• [183]Bartus RT, Elliott PJ, Hayward NJ, Dean RL, Harbeson S, Straub JA, Li Z, Powers JC: Calpain as a novel target for treating acute neurodegenerative disorders. Neurol Res 1995, 17:249-258.
• [184]Wang J, Liu S, Fu Y, Wang JH, Lu Y: Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 2003, 6:1039-1047.
• [185]Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, Simpkins JW: Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 2007, 1772:473-483.
• [186]Zhai DX, Kong QF, Xu WS, Bai SS, Peng HS, Zhao K, Li GZ, Wang DD, Sun B, Wang JH, et al.: RAGE expression is up-regulated in human cerebral ischemia and pMCAO rats. Neurosci Lett 2008, 445:117-121.
• [187]Pichiule P, Chavez JC, Schmidt AM, Vannucci SJ: Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J Biol Chem 2007, 282:36330-36340.
• [188]Taylor CT: Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 2008, 586:4055-4059.
• [189]Taylor CT, Cummins EP: The role of NF-kappaB in hypoxia-induced gene expression. Ann N Y Acad Sci 2009, 1177:178-184.
• [190]O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, et al.: Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 2008, 60:988-1009.
• [191]Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, et al.: Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 2007, 54:721-737.
• [192]Ohyagi Y, Asahara H, Chui DH, Tsuruta Y, Sakae N, Miyoshi K, Yamada T, Kikuchi H, Taniwaki T, Murai H, et al.: Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease. FASEB J 2005, 19:255-257.
• [193]Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T: Changes of p53 in the brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 1997, 232:418-421.
• [194]Checler F, Sunyach C, Pardossi-Piquard R, Sevalle J, Vincent B, Kawarai T, Girardot N, St George-Hyslop P, da Costa CA: The gamma/epsilon-secretase-derived APP intracellular domain fragments regulate p53. Curr Alzheimer Res 2007, 4:423-426.
• [195]Alves da Costa C, Paitel E, Mattson MP, Amson R, Telerman A, Ancolio K, Checler F: Wild-type and mutated presenilins 2 trigger p53-dependent apoptosis and down-regulate presenilin 1 expression in HEK293 human cells and in murine neurons. Proc Natl Acad Sci USA 2002, 99:4043-4048.
• [196]Alves da Costa C, Sunyach C, Pardossi-Piquard R, Sevalle J, Vincent B, Boyer N, Kawarai T, Girardot N, St George-Hyslop P, Checler F: Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J Neurosci 2006, 26:6377-6385.
• [197]Dunys J, Sevalle J, Giaime E, Pardossi-Piquard R, Vitek MP, Renbaum P, Levy-Lahad E, Zhang YW, Xu H, Checler F, da Costa CA: p53-dependent control of transactivation of the Pen2 promoter by presenilins. J Cell Sci 2009, 122:4003-4008.
• [198]Checler F, Dunys J, Pardossi-Piquard R, Alves da Costa C: p53 is regulated by and regulates members of the gamma-secretase complex. Neurodegener Dis 2010, 7:50-55.
• [199]Hunter S, Friedland RP, Brayne C: Time for a change in the research paradigm for Alzheimer's disease: the value of a chaotic matrix modeling approach. CNS Neurosci Ther 2010, 16:254-262.
• [200]Ramsden M, Plant LD, Webster NJ, Vaughan PF, Henderson Z, Pearson HA: Differential effects of unaggregated and aggregated amyloid beta protein (1–40) on K(+) channel currents in primary cultures of rat cerebellar granule and cortical neurones. J Neurochem 2001, 79:699-712.
• [201]Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA: The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci 2003, 23:5531-5535.
• [202]Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, et al.: Beta-amyloid monomers are neuroprotective. J Neurosci 2009, 29:10582-10587.
• [203]Baba A, Mitsumori K, Yamada MK, Nishiyama N, Matsuki N, Ikegaya Y: Beta-amyloid prevents excitotoxicity via recruitment of glial glutamate transporters. Naunyn Schmiedebergs Arch Pharmacol 2003, 368:234-238.
• [204]Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, et al.: Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001, 60:759-767.
• [205]Zou K, Gong JS, Yanagisawa K, Michikawa M: A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 2002, 22:4833-4841.
• [206]Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN: Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 2003, 43:1-16.
• [207]Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA: Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease. Ann N Y Acad Sci 2004, 1019:1-4.
• [208]Armstrong RA: The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis". Int J Alzheimers Dis 2011, 2011:630865.
• [209]Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, Masliah E, Xu H: Alzheimer's beta-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of beta-Amyloid. J Neurosci 2012, 32:11390-11395.
• [210]Luo X, Yan R: Inhibition of BACE1 for therapeutic use in Alzheimer's disease. Int J Clin Exp Pathol 2010, 3:618-628.
• [211]Frautschy SA, Cole GM: Why pleiotropic interventions are needed for Alzheimer's disease. Mol Neurobiol 2010, 41:392-409.
• [212]Jaturapatporn D, Isaac MG, McCleery J, Tabet N: Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev 2012, 2:CD006378.