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AIMS Molecular Science

2016, Volume 3, Issue 2: 138-157. doi: 10.3934/molsci.2016.2.138
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Regulated intramembrane proteolysis, innate immunity and therapeutic targets in Alzheimer’s disease

  • 1.
    Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, Western Gateway Building, Western Road, University College Cork, Cork, Ireland
  • 2.
    Current Address: Department of Zoology, University of Oxford, South Parks Road, Oxford, U.K., OX1 3PS
  • Received: 18 March 2016 Accepted: 15 April 2016 Published: 22 April 2016

  • The critical discovery of the presenilins and their association with familial Alzheimer’s disease (AD) prompted an intensive research effort to understand the molecular mechanisms of that disease. The presenilins were subsequently found to be the catalytic component of the multi-protein enzyme complex, γ-secretase, the enzyme that is known to act on the amyloid precursor protein (APP) to generate amyloid beta (Aβ) peptides that comprise the neuritic plaques implicated in AD pathology. Here, we discuss the background of γ-secretase- mediated proteolysis of APP and its association with familial AD. We discuss the association of neuroinflammation with AD, focusing on the link between the innate immune response, the clearance of the Aβ peptides and disease progression. Currently, there are limited treatments for AD that strive to ameliorate the symptoms of the disease but do not address the molecular basis of the disease. The greater understanding of γ- secretase functions has provided new insights into potential therapeutics for AD, a number of which are in clinical trials.

    Citation: Tara P. Hurst, Caroline Coleman-Vaughan, Indu Patwal, Justin V. McCarthy. Regulated intramembrane proteolysis, innate immunity and therapeutic targets in Alzheimer’s disease[J]. AIMS Molecular Science, 2016, 3(2): 138-157. doi: 10.3934/molsci.2016.2.138

    Related Papers:

  • The critical discovery of the presenilins and their association with familial Alzheimer’s disease (AD) prompted an intensive research effort to understand the molecular mechanisms of that disease. The presenilins were subsequently found to be the catalytic component of the multi-protein enzyme complex, γ-secretase, the enzyme that is known to act on the amyloid precursor protein (APP) to generate amyloid beta (Aβ) peptides that comprise the neuritic plaques implicated in AD pathology. Here, we discuss the background of γ-secretase- mediated proteolysis of APP and its association with familial AD. We discuss the association of neuroinflammation with AD, focusing on the link between the innate immune response, the clearance of the Aβ peptides and disease progression. Currently, there are limited treatments for AD that strive to ameliorate the symptoms of the disease but do not address the molecular basis of the disease. The greater understanding of γ- secretase functions has provided new insights into potential therapeutics for AD, a number of which are in clinical trials.


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    [1] De Strooper B, Saftig P, Craessaerts K, et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387-390. doi: 10.1038/34910
    [2] Jankowsky JL, Fadale DJ, Anderson J, et al. (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13: 159-170. doi: 10.1093/hmg/ddh019
    [3] Clark RF, Hutton M, Fuldner M, et al. (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 11: 219-222. doi: 10.1038/ng1095-219
    [4] Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-356. doi: 10.1126/science.1072994
    [5] Weksler ME, Gouras G, Relkin NR, et al. (2005) The immune system, amyloid-beta peptide, and Alzheimer's disease. Immunol Rev 205: 244-256. doi: 10.1111/j.0105-2896.2005.00264.x
    [6] Hass MR, Sato C, Kopan R, et al. (2009) Presenilin: RIP and beyond. Semin Cell Dev Biol 20: 201-210. doi: 10.1016/j.semcdb.2008.11.014
    [7] de Calignon A, Fox LM, Pitstick R, et al. (2010) Caspase activation precedes and leads to tangles. Nature 464: 1201-1204. doi: 10.1038/nature08890
    [8] Sleegers K, Lambert JC, Bertram L, et al. (2010) The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects. Trends Genet 26: 84-93. doi: 10.1016/j.tig.2009.12.004
    [9] Bertram L, Tanzi RE (2008) Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci 9: 768-778. doi: 10.1038/nrn2494
    [10] Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med2016: e201606210. doi: 10.15252/emmm.201606210
    [11] Jones L, Holmans PA, Hamshere ML, et al. (2010) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One 5: e13950. doi: 10.1371/journal.pone.0013950
    [12] Porcellini E, Carbone I, Ianni M, et al. (2010) Alzheimer's disease gene signature says: beware of brain viral infections. Immun Ageing 7: 16. doi: 10.1186/1742-4933-7-16
    [13] Wozniak MA, Itzhaki RF, Shipley SJ, et al. (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429: 95-100. doi: 10.1016/j.neulet.2007.09.077
    [14] Wozniak MA, Mee AP, Itzhaki RF (2009) Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. J Pathol 217: 131-138. doi: 10.1002/path.2449
    [15] Santana S, Recuero M, Bullido MJ, et al. (2012) Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells. Neurobiol Aging 33: 430.e419-433. doi: 10.1016/j.neurobiolaging.2010.12.010
    [16] Seshadri S, Fitzpatrick AL, Ikram MA, et al. (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303: 1832-1840. doi: 10.1001/jama.2010.574
    [17] Carter CJ (2010) Alzheimer's Disease: A Pathogenetic Autoimmune Disorder Caused by Herpes Simplex in a Gene-Dependent Manner. Int J Alzheimers Dis 2010: 140539. doi: 10.4061/2010/140539
    [18] Tolia A, De Strooper B (2009) Structure and function of γ-secretase. Semin Cell Dev Biol 20: 211-218. doi: 10.1016/j.semcdb.2008.10.007
    [19] Edbauer D, Winkler E, Regula JT, et al. (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5: 486-488. doi: 10.1038/ncb960
    [20] Kimberly WT, LaVoie MJ, Ostaszewski BL, et al. (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 100: 6382-6387. doi: 10.1073/pnas.1037392100
    [21] Takasugi N, Tomita T, Hayashi I, et al. (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature 422: 438-441. doi: 10.1038/nature01506
    [22] Fraering PC, Ye W, Strub JM, et al. (2004) Purification and characterization of the human gamma-secretase complex. Biochemistry 43: 9774-9789. doi: 10.1021/bi0494976
    [23] Winkler E, Hobson S, Fukumori A, et al. (2009) Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretase. Biochemistry 48: 1183-1197. doi: 10.1021/bi801204g
    [24] Sato T, Diehl TS, Narayanan S, et al. (2007) Active gamma-secretase complexes contain only one of each component. J Biol Chem 282: 33985-33993. doi: 10.1074/jbc.M705248200
    [25] Hebert SS, Serneels L, Dejaegere T, et al. (2004) Coordinated and widespread expression of gamma-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol Dis 17: 260-272. doi: 10.1016/j.nbd.2004.08.002
    [26] Shirotani K, Edbauer D, Prokop S, et al. (2004) Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 279: 41340-41345. doi: 10.1074/jbc.M405768200
    [27] Beel AJ, Sanders CR (2008) Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci 65: 1311-1334. doi: 10.1007/s00018-008-7462-2
    [28] Coen K, Annaert W (2010) Presenilins: how much more than gamma-secretase?! Biochem Soc Trans 38: 1474-1478. doi: 10.1042/BST0381474
    [29] McCarthy JV, Twomey C, Wujek P (2009) Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity. Cell Mol Life Sci 66: 1534-1555. doi: 10.1007/s00018-009-8435-9
    [30] Wolfe MS (2009) Intramembrane-cleaving Proteases. J Biol Chem 284: 13969-13973. doi: 10.1074/jbc.R800039200
    [31] Brown MS, Ye J, Rawson RB, et al. (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100: 391-398. doi: 10.1016/S0092-8674(00)80675-3
    [32] McCarthy JV, Twomey C, Wujek P (2009) Presenilin-dependent regulated intramembrane proteolysis and gamma-secretase activity. Cell Mol Life Sci 66: 1534-1555. doi: 10.1007/s00018-009-8435-9
    [33] Chhibber-Goel J, Coleman-Vaughan C, Agrawal V, et al. (2016) gamma-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signalling. J Biol Chem 291: 5971-5985. doi: 10.1074/jbc.M115.679076
    [34] Elzinga BM, Twomey C, Powell JC, et al. (2009) Interleukin-1 receptor type 1 is a substrate for gamma-secretase-dependent regulated intramembrane proteolysis. J Biol Chem 284: 1394-1409.
    [35] Kuhn PH, Marjaux E, Imhof A, et al. (2007) Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase. J Biol Chem 282: 11982-11995. doi: 10.1074/jbc.M700356200
    [36] Chalaris A, Gewiese J, Paliga K, et al. (2010) ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by gamma-secretase. Biochim Biophys Acta 1803: 234-245. doi: 10.1016/j.bbamcr.2009.12.001
    [37] Schulte A, Schulz B, Andrzejewski MG, et al. (2007) Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases. Biochem Biophys Res Commun 358: 233-240. doi: 10.1016/j.bbrc.2007.04.100
    [38] Donoviel DB, Hadjantonakis AK, Ikeda M, et al. (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev 13: 2801-2810. doi: 10.1101/gad.13.21.2801
    [39] Xia X, Qian S, Soriano S, et al. (2001) Loss of presenilin 1 is associated with enhanced beta-catenin signalling and skin tumorigenesis. Proc Natl Acad Sci U S A 98: 10863-10868. doi: 10.1073/pnas.191284198
    [40] Guo Q, Fu W, Sopher BL, et al. (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 5: 101-106. doi: 10.1038/4789
    [41] Feng R, Rampon C, Tang YP, et al. (2001) Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32: 911-926. doi: 10.1016/S0896-6273(01)00523-2
    [42] Wang R, Dineley KT, Sweatt JD, et al. (2004) Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience 126: 305-312. doi: 10.1016/j.neuroscience.2004.03.048
    [43] Herreman A, Hartmann D, Annaert W, et al. (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc Natl Acad Sci U S A 96: 11872-11877. doi: 10.1073/pnas.96.21.11872
    [44] Tournoy J, Bossuyt X, Snellinx A, et al. (2004) Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. Hum Mol Genet 13: 1321-1331. doi: 10.1093/hmg/ddh151
    [45] Maraver A, Tadokoro CE, Badura ML, et al. (2007) Effect of presenilins in the apoptosis of thymocytes and homeostasis of CD8+ T cells. Blood 110: 3218-3225. doi: 10.1182/blood-2007-01-070359
    [46] Laky K, Fowlkes BJ (2007) Presenilins regulate αβ T cell development by modulating TCR signalling. J Exp Med 204: 2115-2129. doi: 10.1084/jem.20070550
    [47] Yagi T, Giallourakis C, Mohanty S, et al. (2008) Defective signal transduction in B lymphocytes lacking presenilin proteins. Proc Natl Acad Sci U S A 105: 979-984. doi: 10.1073/pnas.0707755105
    [48] Beglopoulos V, Sun X, Saura CA, et al. (2004) Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 279: 46907-46914. doi: 10.1074/jbc.M409544200
    [49] Jayadev S, Case A, Eastman AJ, et al. (2010) Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release. PLoS ONE 5: e15743. doi: 10.1371/journal.pone.0015743
    [50] Glenn G, van der Geer P (2008) Toll-like receptors stimulate regulated intramembrane proteolysis of the CSF-1 receptor through Erk activation. FEBS Lett 582: 911-915. doi: 10.1016/j.febslet.2008.02.029
    [51] Garlind A, Brauner A, Hojeberg B, et al. (1999) Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal fluid in Alzheimer's disease patients. Brain Res 826: 112-116. doi: 10.1016/S0006-8993(99)01092-6
    [52] Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117: 3720-3732. doi: 10.1182/blood-2010-07-273417
    [53] Twomey C, Qian S, McCarthy JV (2009) TRAF6 promotes ubiquitination and regulated intramembrane proteolysis of IL-1R1. Biochem Biophys Res Commun 381: 418-423. doi: 10.1016/j.bbrc.2009.02.051
    [54] Powell JC, Twomey C, Jain R, et al. (2009) Association between Presenilin-1 and TRAF6 modulates regulated intramembrane proteolysis of the p75NTR neurotrophin receptor. J Neurochem 108: 216-230. doi: 10.1111/j.1471-4159.2008.05763.x
    [55] Curtis BM, Widmer MB, deRoos P, et al. (1990) IL-1 and its receptor are translocated to the nucleus. J Immunol 144: 1295-1303.
    [56] Levine SJ (2008) Molecular Mechanisms of Soluble Cytokine Receptor Generation. J Biol Chem 283: 14177-14181. doi: 10.1074/jbc.R700052200
    [57] Frykman S, Hur JY, Franberg J, et al. (2010) Synaptic and endosomal localization of active gamma-secretase in rat brain. PLoS One 5: e8948. doi: 10.1371/journal.pone.0008948
    [58] Meckler X, Checler F (2016) Presenilin 1 and Presenilin 2 Target gamma-Secretase Complexes to Distinct Cellular Compartments. J Biol ChemM115: 708297.
    [59] Doody RS, Raman R, Farlow M, et al. (2013) A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 369: 341-350. doi: 10.1056/NEJMoa1210951
    [60] Goodbourn S, Didcock L, Randall RE (2000) Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81: 2341-2364. doi: 10.1099/0022-1317-81-10-2341
    [61] Saleh AZ, Fang AT, Arch AE, et al. (2004) Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor. Oncogene 23: 7076-7086. doi: 10.1038/sj.onc.1207955
    [62] Garton KJ, Gough PJ, Raines EW (2006) Emerging roles for ectodomain shedding in the regulation of inflammatory responses. J Leukoc Biol 79: 1105-1116. doi: 10.1189/jlb.0106038
    [63] Mambole A, Baruch D, Nusbaum P, et al. (2008) The cleavage of neutrophil leukosialin (CD43) by cathepsin G releases its extracellular domain and triggers its intramembrane proteolysis by presenilin/gamma-secretase. J Biol Chem 283: 23627-23635. doi: 10.1074/jbc.M710286200
    [64] Cui W, Ke JZ, Zhang Q, et al. (2006) The intracellular domain of CD44 promotes the fusion of macrophages. Blood 107: 796-805. doi: 10.1182/blood-2005-05-1902
    [65] Carey BW, Kim DY, Kovacs DM (2007) Presenilin/gamma-secretase and alpha-secretase-like peptidases cleave human MHC Class I proteins. Biochem J 401: 121-127. doi: 10.1042/BJ20060847
    [66] Bonifati DM, Kishore U (2007) Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44: 999-1010. doi: 10.1016/j.molimm.2006.03.007
    [67] Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48: 1592-1603. doi: 10.1016/j.molimm.2011.04.003
    [68] Fonseca MI, Chu SH, Berci AM, et al. (2011) Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease. J Neuroinflammation 8: 4. doi: 10.1186/1742-2094-8-4
    [69] Webster SD, Galvan MD, Ferran E, et al. (2001) Antibody-Mediated Phagocytosis of the Amyloid β-Peptide in Microglia Is Differentially Modulated by C1q. J Immunol 166: 7496-7503. doi: 10.4049/jimmunol.166.12.7496
    [70] Fonseca MI, Zhou J, Botto M, et al. (2004) Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci 24: 6457-6465. doi: 10.1523/JNEUROSCI.0901-04.2004
    [71] Fraser DA, Pisalyaput K, Tenner AJ (2010) C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem 112: 733-743. doi: 10.1111/j.1471-4159.2009.06494.x
    [72] Rogers J, Li R, Mastroeni D, et al. (2006) Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging 27: 1733-1739. doi: 10.1016/j.neurobiolaging.2005.09.043
    [73] Akiyama H, Barger S, Barnum S, et al. (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421. doi: 10.1016/S0197-4580(00)00124-X
    [74] Spitzer P, Herrmann M, Klafki H-W, et al. (2010) Phagocytosis and LPS alter the maturation state of β-amyloid precursor protein and induce different Aβ peptide release signatures in human mononuclear phagocytes. J Neuroinflammation 7: 59-59. doi: 10.1186/1742-2094-7-59
    [75] Morgan D, Gordon MN, Tan J, et al. (2005) Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 64: 743-753. doi: 10.1097/01.jnen.0000178444.33972.e0
    [76] Streit WJ (2004) Microglia and Alzheimer's disease pathogenesis. J Neurosci Res 77: 1-8. doi: 10.1002/jnr.20093
    [77] Trudler D, Farfara D, Frenkel D (2010) Toll-Like Receptors Expression and Signalling in Glia Cells in Neuro-Amyloidogenic Diseases: Towards Future Therapeutic Application. Mediators of Inflammation 2010: 12.
    [78] Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30: 16-34. doi: 10.3109/08830185.2010.529976
    [79] Carty M, Bowie AG (2011) Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol 81: 825-837. doi: 10.1016/j.bcp.2011.01.003
    [80] Chen F, Hasegawa H, Schmitt-Ulms G, et al. (2006) TMP21 is a presenilin complex component that modulates [gamma]-secretase but not [epsiv]-secretase activity. Nature 440: 1208-1212. doi: 10.1038/nature04667
    [81] Iribarren P, Chen K, Hu J, et al. (2005) CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1-42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2. FASEBJ 19: 2032-2034.
    [82] Jin JJ, Kim HD, Maxwell JA, et al. (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 5: 23. doi: 10.1186/1742-2094-5-23
    [83] Herber DL, Mercer M, Roth LM, et al. (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2: 222-231. doi: 10.1007/s11481-007-9069-z
    [84] DiCarlo G, Wilcock D, Henderson D, et al. (2001) Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol Aging 22: 1007-1012. doi: 10.1016/S0197-4580(01)00292-5
    [85] Richard KL, Filali M, Prefontaine P, et al. (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J Neurosci 28: 5784-5793. doi: 10.1523/JNEUROSCI.1146-08.2008
    [86] Jana M, Palencia CA, Pahan K (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. J Immunol 181: 7254-7262. doi: 10.4049/jimmunol.181.10.7254
    [87] Frank S, Copanaki E, Burbach GJ, et al. (2009) Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453: 41-44. doi: 10.1016/j.neulet.2009.01.075
    [88] Michaud J-P, Richard KL, Rivest S (2011) MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. Mol Neurodegener 6: 5-5. doi: 10.1186/1750-1326-6-5
    [89] Cui JG, Li YY, Zhao Y, et al. (2010) Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem 285: 38951-38960. doi: 10.1074/jbc.M110.178848
    [90] Standridge JB (2006) Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. Curr Alzheimer Res 3: 95-108. doi: 10.2174/156720506776383068
    [91] Lue LF, Walker DG, Rogers J (2001) Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures. Neurobiol Aging 22: 945-956. doi: 10.1016/S0197-4580(01)00311-6
    [92] Yan Q, Zhang J, Liu H, et al. (2003) Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 23: 7504-7509.
    [93] Yamamoto M, Kiyota T, Horiba M, et al. (2007) Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice. Am J Pathol 170: 680-692. doi: 10.2353/ajpath.2007.060378
    [94] Kong Q, Peterson TS, Baker O, et al. (2009) Interleukin-1beta enhances nucleotide-induced and alpha-secretase-dependent amyloid precursor protein processing in rat primary cortical neurons via up-regulation of the P2Y(2) receptor. J Neurochem 109: 1300-1310. doi: 10.1111/j.1471-4159.2009.06048.x
    [95] Sheng JG, Zhu SG, Jones RA, et al. (2000) Interleukin-1 Promotes Expression and Phosphorylation of Neurofilament and tau Proteins in Vivo. Exp Neurol 163: 388-391. doi: 10.1006/exnr.2000.7393
    [96] Moses GS, Jensen MD, Lue LF, et al. (2006) Secretory PLA2-IIA: a new inflammatory factor for Alzheimer's disease. J Neuroinflammation 3: 28. doi: 10.1186/1742-2094-3-28
    [97] Rezai-Zadeh K, Gate D, Gowing G, et al. (2011) How to Get from Here to There: Macrophage Recruitment in Alzheimer's Disease. Curr Alzheimer Res 8: 156-163. doi: 10.2174/156720511795256017
    [98] Shaftel SS, Kyrkanides S, Olschowka JA, et al. (2007) Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117: 1595-1604. doi: 10.1172/JCI31450
    [99] Rogers J, Strohmeyer R, Kovelowski CJ, et al. (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40: 260-269. doi: 10.1002/glia.10153
    [100] Jutras I, Laplante A, Boulais J, et al. (2005) Gamma-secretase is a functional component of phagosomes. J Biol Chem 280: 36310-36317. doi: 10.1074/jbc.M504069200
    [101] Kiyota T, Yamamoto M, Xiong H, et al. (2009) CCL2 Accelerates Microglia-Mediated Aβ Oligomer Formation and Progression of Neurocognitive Dysfunction. PLoS ONE 4: e6197. doi: 10.1371/journal.pone.0006197
    [102] El Khoury J, Toft M, Hickman SE, et al. (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13: 432-438. doi: 10.1038/nm1555
    [103] De Strooper B, Chavez Gutierrez L (2015) Learning by failing: ideas and concepts to tackle gamma-secretases in Alzheimer's disease and beyond. Annu Rev Pharmacol Toxicol 55: 419-437. doi: 10.1146/annurev-pharmtox-010814-124309
    [104] Beher D, Clarke EE, Wrigley JD, et al. (2004) Selected non-steroidal anti-inflammatory drugs and their derivatives target gamma-secretase at a novel site. Evidence for an allosteric mechanism. J Biol Chem 279: 43419-43426.
    [105] Kukar T, Golde TE (2008) Possible mechanisms of action of NSAIDs and related compounds that modulate gamma-secretase cleavage. Curr Top Med Chem 8: 47-53. doi: 10.2174/156802608783334042
    [106] Wong GT, Manfra D, Poulet FM, et al. (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279: 12876-12882. doi: 10.1074/jbc.M311652200
    [107] Jack C, Berezovska O, Wolfe MS, et al. (2001) Effect of PS1 deficiency and an APP gamma-secretase inhibitor on Notch1 signalling in primary mammalian neurons. Brain Res Mol Brain Res 87: 166-174. doi: 10.1016/S0169-328X(01)00010-9
    [108] Geling A, Steiner H, Willem M, et al. (2002) A gamma-secretase inhibitor blocks Notch signalling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep 3: 688-694. doi: 10.1093/embo-reports/kvf124
    [109] Micchelli CA, Esler WP, Kimberly WT, et al. (2003) Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila. FASEB J 17: 79-81.
    [110] Henley DB, Sundell KL, Sethuraman G, et al. (2014) Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings. Curr Med Res Opin 30: 2021-2032. doi: 10.1185/03007995.2014.939167
    [111] Panza F, Frisardi V, Imbimbo BP, et al. (2010) REVIEW: gamma-Secretase inhibitors for the treatment of Alzheimer's disease: The current state. CNS Neurosci Ther 16: 272-284. doi: 10.1111/j.1755-5949.2010.00164.x
    [112] Frisardi V, Solfrizzi V, Imbimbo PB, et al. (2010) Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid. Curr Alzheimer Res 7: 40-55. doi: 10.2174/156720510790274400
    [113] Bergmans BA, De Strooper B (2010) gamma-secretases: from cell biology to therapeutic strategies. Lancet Neurol 9: 215-226. doi: 10.1016/S1474-4422(09)70332-1
    [114] Samson K (2010) NerveCenter: Phase III Alzheimer trial halted: Search for therapeutic biomarkers continues. Ann Neurol 68: A9-a12.
    [115] Gillman KW, Starrett JE, Jr., Parker MF, et al. (2010) Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor. ACS Med Chem Lett 1: 120-124. doi: 10.1021/ml1000239
    [116] De Strooper B (2014) Lessons from a failed gamma-secretase Alzheimer trial. Cell 159: 721-726. doi: 10.1016/j.cell.2014.10.016
    [117] Cummings J (2010) What Can Be Inferred from the Interruption of the Semagacestat Trial for Treatment of Alzheimer's Disease? Biol Psychiatry 68: 876-878. doi: 10.1016/j.biopsych.2010.09.020
    [118] Qyang Y, Chambers SM, Wang P, et al. (2004) Myeloproliferative disease in mice with reduced presenilin gene dosage: effect of gamma-secretase blockage. Biochemistry 43: 5352-5359. doi: 10.1021/bi049826u
    [119] Imbimbo BP (2008) Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 8: 54-61. doi: 10.2174/156802608783334015
    [120] Pul R, Dodel R, Stangel M (2011) Antibody-based therapy in Alzheimer's disease. Expert Opin Biol Ther 11: 343-357. doi: 10.1517/14712598.2011.552884
    [121] Sarazin M, Dorothee G, de Souza LC, et al. (2013) Immunotherapy in Alzheimer's disease: do we have all the pieces of the puzzle? Biol Psychiatry 74: 329-332. doi: 10.1016/j.biopsych.2013.04.011
    [122] Brodaty H, Breteler MM, Dekosky ST, et al. (2011) The world of dementia beyond 2020. J Am Geriatr Soc 59: 923-927. doi: 10.1111/j.1532-5415.2011.03365.x
    [123] Yamada K, Yabuki C, Seubert P, et al. (2009) Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J Neurosci 29: 11393-11398. doi: 10.1523/JNEUROSCI.2021-09.2009
    [124] Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid-[beta] attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177. doi: 10.1038/22124
    [125] Lemere CA, Spooner ET, Leverone JF, et al. (2003) Amyloid-beta immunization in Alzheimer's disease transgenic mouse models and wildtype mice. Neurochem Res 28: 1017-1027. doi: 10.1023/A:1023203122036
    [126] Fu HJ, Liu B, Frost JL, et al. (2010) Amyloid-beta immunotherapy for Alzheimer's disease. CNS Neurol Disord Drug Targets 9: 197-206. doi: 10.2174/187152710791012017
    [127] Robert R, Dolezal O, Waddington L, et al. (2009) Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers. Protein Eng Des Sel 22: 199-208.
    [128] Marin-Argany M, Rivera-Hernandez G, Marti J, et al. (2011) An anti-Abeta (amyloid beta) single-chain variable fragment prevents amyloid fibril formation and cytotoxicity by withdrawing Abeta oligomers from the amyloid pathway. Biochem J 437: 25-34. doi: 10.1042/BJ20101712
    [129] Panza F, Frisardi V, Imbimbo BP, et al. (2011) Anti-beta-amyloid immunotherapy for Alzheimer's disease: focus on bapineuzumab. Curr Alzheimer Res 8: 808-817. doi: 10.2174/156720511798192718
    [130] Lambracht-Washington D, Qu BX, Fu M, et al. (2011) DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer's disease as it diminishes antigen-specific Th1 and Th17 cell proliferation. Cell Mol Neurobiol 31: 867-874. doi: 10.1007/s10571-011-9680-7
    [131] Salloway S, Sperling R, Brashear HR (2014) Phase 3 trials of solanezumab and bapineuzumab for Alzheimer's disease. N Engl J Med 370: 1460. doi: 10.1056/NEJMc1402193
    [132] Salloway S, Sperling R, Fox NC, et al. (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 370: 322-333. doi: 10.1056/NEJMoa1304839
    [133] Krishnamurthy PK, Sigurdsson EM (2011) Therapeutic applications of antibodies in non-infectious neurodegenerative diseases. New Biotechnol 28: 511-517. doi: 10.1016/j.nbt.2011.03.020
    [134] Britschgi M, Wyss-Coray T (2009) Blood protein signature for the early diagnosis of Alzheimer disease. Arch Neurol 66: 161-165. doi: 10.1001/archneurol.2008.530
    [135] Lindberg C, Chromek M, Ahrengart L, et al. (2005) Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's disease. Neurochem Int 46: 551-557. doi: 10.1016/j.neuint.2005.01.004
    [136] Reddy MM, Wilson R, Wilson J, et al. (2011) Identification of Candidate IgG Biomarkers for Alzheimer's Disease via Combinatorial Library Screening. Cell 144: 132-142. doi: 10.1016/j.cell.2010.11.054
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