Biochemistry (Moscow)

, Volume 80, Issue 13, pp 1800–1819 | Cite as

Beta-Amyloid and Tau-Protein: Structure, Interaction, and Prion-Like Properties

  • O. G. TatarnikovaEmail author
  • M. A. Orlov
  • N. V. Bobkova


During the last twenty years, molecular genetic investigations of Alzheimer’s disease (AD) have significantly broadened our knowledge of basic mechanisms of this disorder. However, still no unambiguous concept on the molecular bases of AD pathogenesis has been elaborated, which significantly impedes the development of AD therapy. In this review, we analyze issues concerning processes of generation of two proteins (β-amyloid peptide and Tau-protein) in the cell, which are believed to play the key role in AD genesis. Until recently, these agents were considered independently of each other, but in light of the latest studies, it becomes clear that it is necessary to study their interaction and combined effects. Studies of mechanisms of toxic action of these endogenous compounds, beginning from their interaction with known receptors of main neurotransmitters to specific peculiarities of functioning of signal intracellular pathways upon development of this pathology, open the way to development of new pharmaceutical substances directed concurrently on key mechanisms of interaction of toxic proteins inside the cell and on the pathways of their propagation in the extracellular space.

Key words

Alzheimer’s disease β-amyloid Tau-protein APP presenilins prion-like mechanism of AD 


beta-amyloid peptide


Alzheimer’s disease


a desintegrin and metalloproteinase domain


amyloid precursor protein intracellular domain


apolipoprotein E


amyloid precursor protein


beta-site amyloid precursor protein cleaving enzyme


C-terminal fragment


familial Alzheimer’s disease


γ-secretase modulator


liver X receptor


microtubule-associated protein tau


neurofibrillary tangles


primary age-related tauopathy


paired helical filaments


peroxisome proliferator-activated receptor γ


prion protein




receptor for advanced glycation end products


retinoid X receptor


single-nucleotide polymorphism.


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  1. 1.
    Duthey, B. (2013) Background paper. Alzheimer’s disease and other dementias, in A Public Health Approach to Innovation, Update on 2004 Background Paper, pp. 1–74.Google Scholar
  2. 2.
    Lee, V., Goedert, M., and Trojanowski, J. (2001) Neurode-generative tauopathies, Annu. Rev. Neurosci., 24, 1121–1159.PubMedCrossRefGoogle Scholar
  3. 3.
    Jayadev, S., Nochlin, D., Poorkaj, P., Steinbart, E., Mastrianni, J., Montine, T., Ghetti, B., Schellenberg, G., Bird, T., and Leverenz, J. (2011) Familial prion disease with Alzheimer’s disease-like tau pathology and clinical pheno-type, Ann. Neurol., 69, 712–720.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Hardy, J., and Selkoe, D. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics, Science, 297, 353–356.PubMedCrossRefGoogle Scholar
  5. 5.
    Ryazantseva, M. A., Mozhaeva, G. N., and Kaznacheeva, E. V. (2014) The pathogenesis of Alzheimer’s disease and potassium homeostasis, in Neurodegenerative Diseases: from Genome to the Whole Organism (Ugrumov, M. V., ed.) Vol. 2, Nauka, Moscow, pp. 163–181.Google Scholar
  6. 6.
    Le, M., Kim, W., Lee, S., McKee, A., and Hall, G. (2012) Multiple mechanisms of extracellular tau spreading in a non-transgenic tauopathy model, Am. J. Neurodegener. Dis., 1, 316–333.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Avila, J., Lucas, J., Perez, M., and Hernandez, F. (2004) Role of tau protein in both physiological and pathological conditions, Physiol. Rev., 84, 361–384.PubMedCrossRefGoogle Scholar
  8. 8.
    Schliebs, R., and Arendt, T. (2006) The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease, J. Neural Transm., 113, 1625–1644.PubMedCrossRefGoogle Scholar
  9. 9.
    Crow, T., Cross, A., Cooper, S., Deakin, J., Ferrier, I., Johnson, J., Joseph, M., Owen, F., Poulter, M., Lofthouse, R., Corsellis, J., Chambers, D., Blessed, G., Perry, E., Perry, R., and Tomlinson, B. (1984) Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides, Neuropharmacology, 23, 1561–1569.PubMedCrossRefGoogle Scholar
  10. 10.
    Brouwers, N., Sleegers, K., and Van Broeckhoven, C. (2008) Molecular genetics of Alzheimer’s disease: an update, Ann. Med., 40, 562–583.PubMedCrossRefGoogle Scholar
  11. 11.
    Barger, S., DeWall, K., Liu, L., Mrak, R., and Griffin, W. (2008) Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in prox-imity to Alzheimer’s beta-amyloid plaques: potential expla-nations from cell culture studies, J. Neuropathol. Exp. Neurol., 67, 773–783.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Holtzman, D., Herz, J., and Bu, G. (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer’s disease, Cold Spring Harb. Perspect. Med., 2, a006312.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Bertram, L., and Tanzi, R. (2008) Thirty years of Alzheimer’s disease genetics: the implications of systemat-ic meta-analyses, Nat. Rev. Neurosci., 9, 768–778.PubMedCrossRefGoogle Scholar
  14. 14.
    Weller, R., Yow, H., Preston, S., Mazanti, I., and Nicoll, J. (2002) Cerebrovascular disease is a major factor in the fail-ure of elimination of amyloid beta from the aging human brain, Ann. N. Y. Acad. Sci., 977, 162–168.PubMedCrossRefGoogle Scholar
  15. 15.
    Carson, J., and Turner, A. (2002) Beta-amyloid catabolism: role for neprilysin (NEP) and other metallopeptidases? J. Neurochem., 81, 1–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Nalivaeva, N., Fisk, L., Belyaev, N., and Turner, A. (2008) Amyloid-degrading enzymes as therapeutic targets in Alzheimer’s disease, Curr. Alzheimer Res., 5, 212–224.PubMedCrossRefGoogle Scholar
  17. 17.
    Fisk, L., Nalivaeva, N., Boyle, J., Peers, C., and Turner, A. (2007) Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurons and astrocytes, Neurochem. Res., 32, 1741–1748.PubMedCrossRefGoogle Scholar
  18. 18.
    Dubrovskaya, N., Nalivaeva, N., Plesneva, S., Feponova, A., Turner, A., and Zhuravin, I. (2010) Changes in the activity of amyloid-degrading metallopeptidases leads to disruption of memory in rats, Neurosci. Behav. Physiol., 40, 975–980.CrossRefGoogle Scholar
  19. 19.
    Bohm, C., Chen, F., Sevalle, J., Qamar, S., Dodd, R., Li, Y., and St. George-Hyslop, P. H. (2015) Current and future implications of basic and translational research on amy-loid-β peptide production and removal pathways, Mol. Cell. Neurosci., 66, 3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Ray, B., Long, J., Sokol, D., and Lahiri, D. (2011) Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker, PLoS One, 6, e20405.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Asai, M., Hattori, C., Szabo, B., Sasagawa, N., Maruyama, K., Tanuma, S., and Ishiura, S. (2003) Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secre-tase, Biochem. Biophys. Res. Commun., 301, 231–235.PubMedCrossRefGoogle Scholar
  22. 22.
    Fahrenholz, F., Gilbert, S., Kojro, E., Lammich, S., and Postina, R. (2000) Alpha-secretase activity of the disinte-grin metalloprotease ADAM 10. Influences of domain structure, Ann. N. Y. Acad. Sci., 920, 215–222.PubMedCrossRefGoogle Scholar
  23. 23.
    Fuwa, H., Takahashi, Y., Konno, Y., Watanabe, N., Miyashita, H., Sasaki, M., Natsugari, H., Kan, T., Fukuyama, T., Tomita, T., and Iwatsubo, T. (2007) Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-sec-retase inhibitors, ACS Chem. Biol., 2, 408–418.PubMedCrossRefGoogle Scholar
  24. 24.
    Suh, J., Choi, S., Romano, D., Gannon, M., Lesinski, A., Kim, D., and Tanzi, R. (2013) ADAM10 missense muta-tions potentiate β-amyloid accumulation by impairing prodomain chaperone function, Neuron, 80, 385–401.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Vassar, R., Kuhn, P., Haass, C., Kennedy, M., Rajendran, L., Wong, P., and Lichtenthaler, S. (2014) Function, thera-peutic potential and cell biology of BACE proteases: cur-rent status and future prospects, J. Neurochem., 130, 4–28.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Rogaeva, E., Meng, Y., Lee, J., Gu, Y., Kawarai, T., Zou, F., Katayama, T., Baldwin, C., Cheng, R., Hasegawa, H., Chen, F., Shibata, N., Lunetta, K., Pardossi-Piquard, R., Bohm, C., Wakutani, Y., Cupples, A., Cuenco, K., Green, R., Pinessi, L., Rainero, I., Sorbi, S., Bruni, A., Duara, R., Friedland, R., Inzelberg, R., Hampe, W., Bujo, H., Song, Y., Andersen, O., Willnow, T., Graff-Radford, N., Petersen, R., Dickson, D., Der, S., Fraser, P., Schmitt-Ulms, G., Younkin, S., Mayeux, R., Farrer, L., and St. George-Hyslop, P. (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer’s disease, Nat. Genet., 39, 168–177.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bhalla, A., Vetanovetz, C., Morel, E., Chamoun, Z., Di Paolo, G., and Small, S. (2012) The location and traffick-ing routes of the neuronal retromer and its role in amyloid precursor protein transport, Neurobiol. Dis., 47, 126–134.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Seaman, M. (2012) The retromer complex–endosomal protein recycling and beyond, J. Cell Sci., 125, 4693–4702.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vardarajan, B., Bruesegem, S., Harbour, M., Inzelberg, R., Friedland, R., St. George-Hyslop, P., Seaman, M., and Farrer, L. (2012) Identification of Alzheimer disease-asso-ciated variants in genes that regulate retromer function, Neurobiol. Aging, 33, e15–2231.PubMedCrossRefGoogle Scholar
  30. 30.
    Edbauer, D., Winkler, E., Regula, J., Pesold, B., Steiner, H., and Haass, C. (2003) Reconstitution of gamma-secre-tase activity, Nat. Cell Biol., 5, 486–488.PubMedCrossRefGoogle Scholar
  31. 31.
    Sobhanifar, S., Schneider, B., Lohr, F., Gottstein, D., Ikeya, T., Mlynarczyk, K., Pulawski, W., Ghoshdastider, U., Kolinski, M., Filipek, S., Guntert, P., Bernhard, F., and Dotsch, V. (2010) Structural investigation of the C-ter-minal catalytic fragment of presenilin 1, Proc. Natl. Acad. Sci. USA, 5, 9644–9649.CrossRefGoogle Scholar
  32. 32.
    De Strooper, B. (2003) Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-secretase complex, Neuron, 10, 9–12.CrossRefGoogle Scholar
  33. 33.
    Glenner, G., and Wong, C. (1984) Alzheimer’s disease: ini-tial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun., 120, 885–890.PubMedCrossRefGoogle Scholar
  34. 34.
    Bekris, L., Yu. C., Bird, T., and Tsuang, D. (2010) Genetics of Alzheimer’s disease, J. Geriatr. Psychiatr. Neurol., 23, 213–227.CrossRefGoogle Scholar
  35. 35.
    Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerriere, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M., Dubas, F., Frebourg, T., and Campion, D. (2006) APP locus duplication causes autoso-mal dominant early-onset Alzheimer’s disease with cere-bral amyloid angiopathy, Nat. Genet., 38, 24–26.PubMedCrossRefGoogle Scholar
  36. 36.
    Bornemann, K., and Staufenbiel, M. (2000) Transgenic mouse models of Alzheimer’s disease, Ann. N. Y. Acad. Sci., 908, 260–266.PubMedCrossRefGoogle Scholar
  37. 37.
    Nilsberth, C., Westlind-Danielsson, A., Eckman, C., Condron, M., Axelman, K., Forsell, C., Stenh, C., Luthman, J., Teplow, D., Younkin, S., and Lannfelt, L. (2001) The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta-protofibril forma-tion, Nat. Neurosci., 4, 887–893.PubMedCrossRefGoogle Scholar
  38. 38.
    Cruchaga, C., Karch, C., Jin, S., Benitez, B., Cai, Y., Guerreiro, R., Harari, O., Norton, J., Budde, J., Bertelsen, S., Jeng, A., Cooper, B., Skorupa, T., Carrell, D., Levitch, D., Hsu, S., Choi, J., Ryten, M., Hardy, J., Ryten, M., Trabzuni, D., Weale, M., Ramasamy, A., Smith, C., Sassi, C., Bras, J., Gibbs, J., Hernandez, D., Lupton, M., Powell, J., Forabosco, P., Ridge, P., Corcoran, C., Tschanz, J., Norton, M., Munger, R., Schmutz, C., Leary, M., Demirci, F., Bamne, M., Wang, X., Lopez, O., Ganguli, M., Medway, C., Turton, J., Lord, J., Braae, A., Barber, I., Brown, K., Passmore, P., Craig, D., Johnston, J., McGuinness, B., Todd, S., Heun, R., Kolsch, H., Kehoe, P., Hooper, N., Vardy, E., Mann, D., Pickering-Brown, S., Brown, K., Kalsheker, N., Lowe, J., Morgan, K., David, S., Wilcock, G., Warden, D., Holmes, C., Pastor, P., Lorenzo-Betancor, O., Brkanac, Z., Scott, E., Topol, E., Morgan, K., Rogaeva, E., Singleton, A., Hardy, J., Kamboh, M., St. George-Hyslop, P., Cairns, N., Morris, J., Kauwe, J., and Goate, A. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s dis-ease, Nature, 505, 550–554.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J., Amouyel, P., Goate, A., Rademakers, R., Morgan, K., Powell, J., St. George-Hyslop, P., Singleton, A., Hardy, J., and Alzheimer’s Genetic Analysis Group (2013) TREM2 vari-ants in Alzheimer’s disease, N. Engl. J. Med., 368, 117–127.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M., Pahwa, J., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A., Lovestone, S., Powell, J., Proitsi, P., Lupton, M., Brayne, C., Rubinsztein, D., Gill, M., Lawlor, B., Lynch, A., Morgan, K., Brown, K., Passmore, P., Craig, D., McGuinness, B., Todd, S., Holmes, C., Mann, D., Smith, A., Love, S., Kehoe, P., Hardy, J., Mead, S., Fox, N., Rossor, M., Collinge, J., Maier, W., Jessen, F., Schurmann, B., Heun, R., Bussche, H., Heuser, I., Kornhuber, J., Wiltfang, J., Dichgans, M., Frolich, L., Hampel, H., Hull, M., Rujescu, D., Goate, A., Kauwe, J., Cruchaga, C., Nowotny, P., Morris, J., Mayo, K., Sleegers, K., Bettens, K., Engelborghs, S., De Deyn, P., Broeckhoven, C., Livingston, G., Bass, N., Gurling, H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C., Tsolaki, M., Singleton, A., Guerreiro, R., Muhleisen, T., Nothen, M., Moebus, S., Jockel, K., Klopp, N., Wichmann, H., Carrasquillo, M., Pankratz, V., Younkin, S., Holmans, P., O’Donovan, M., Owen, M., and Williams, J. (2009) Genome-wide association study identi-fies variants at CLU and PICALM associated with Alzheimer’s disease, Nat. Genet., 4, 1088–1093.CrossRefGoogle Scholar
  41. 41.
    Hoglinger, G., Melhem, N., Dickson, D., Sleiman, P., Wang, L., Klei, L., Rademakers, R., de Silva, R., Litvan, I., Riley, D., Swieten, J., Heutink, P., Wszolek, Z., Uitti, R., Vandrovcova, J., Hurtig, H., Gross, R., Maetzler, W., Goldwurm, S., Tolosa, E., Borroni, B., Pastor, P., Cantwell, L., Han, M., Dillman, A., Brug, M., Gibbs, J., Cookson, M., Hernandez, D., Singleton, A., Farrer, M., Yu, C., Golbe, L., Revesz, T., Hardy, J., Lees, A., Devlin, B., Hakonarson, H., Muller, U., and Schellenberg, G. (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy, Nat. Genet., 43, 699–705.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lambert, J., Ibrahim-Verbaas, C., Harold, D., Naj, A., Sims, R., Bellenguez, C., Jun, G., Destefano, A., Bis, J., Beecham, G., Grenier-Boley, B., Russo, G., Thorton-Wells, T., Jones, N., Smith, A., Chouraki, V., Thomas, C., Ikram, M., Zelenika, D., Vardarajan, B., Kamatani, Y., Lin, C., Gerrish, A., Schmidt, H., Kunkle, B., Dunstan, M., Ruiz, A., Bihoreau, M., Choi, S., Reitz, C., Pasquier, F., Cruchaga, C., Craig, D., Amin, N., Berr, C., Lopez, O., De Jager, P., Deramecourt, V., Johnston, J., Evans, D., Lovestone, S., Letenneur, L., Moron, F., Rubinsztein, D., Eiriksdottir, G., Sleegers, K., Goate, A., Fievet, N., Huentelman, M., Gill, M., Brown, K., Kamboh, M., Keller, L., Barberger-Gateau, P., McGuiness, B., Larson, E., Green, R., Myers, A., Dufouil, C., Todd, S., Wallon, D., Love, S., Rogaeva, E., Gallacher, J., St. George-Hyslop, P., Clarimon, J., Lleo, A., Bayer, A., Tsuang, D., Yu, L., Tsolaki, M., Bossu, P., Spalletta, G., Proitsi, P., Collinge, J., Sorbi, S., Sanchez-Garcia, F., Fox, N., Hardy, J., Deniz Naranjo M., Bosco, P., Clarke, R., Brayne, C., Galimberti, D., Mancuso, M., Matthews, F., European Alzheimer’s Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer’s Disease, Alzheimer’s Disease Genetic Consortium, and Cohorts for Heart and Aging Research in Genomic Epidemiology (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease, Nat. Genet., 45, 1452–1458.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Naj, A., Jun, G., Beecham, G., Wang, L., Vardarajan, B., Buros, J., Gallins, P., Buxbaum, J., Jarvik, G., Crane, P., Larson, E., Bird, T., Boeve, B., Graff-Radford, N., De Jager, P., Evans, D., Schneider, J., Carrasquillo, M., Ertekin-Taner, N., Younkin, S., Cruchaga, C., Kauwe, J., Nowotny, P., Kramer, P., Hardy, J., Huentelman, M., Myers, A., Barmada, M., Demirci, F., Baldwin, C., Green, R., Rogaeva, E., St. George-Hyslop, P., Arnold, S., Barber, R., Beach, T., Bigio, E., Bowen, J., Boxer, A., Burke, J., Cairns, N., Carlson, C., Carney, R., Carroll, S., Chui, H., Clark, D., Corneveaux, J., Cotman, C., Cummings, J., DeCarli, C., DeKosky, S., Diaz-Arrastia, R., Dick, M., Dickson, D., Ellis, W., Faber, K., Fallon, K., Farlow, M., Ferris, S., Frosch, M., Galasko, D., Ganguli, M., Gearing, M., Geschwind, D., Ghetti, B., Gilbert, J., Gilman, S., Giordani, B., Glass, J., Growdon, J., Hamilton, R., Harrell, L., Head, E., Honig, L., Hulette, C., Hyman, B., Jicha, G., Jin, L., Johnson, N., Karlawish, J., Karydas, A., Kaye, J., Kim, R., Koo, E., Kowall, N., Lah, J., Levey, A., Lieberman, A., Lopez, O., Mack, W., Marson, D., Martiniuk, F., Mash, D., Masliah, E., McCormick, W., McCurry, S., McDavid, A., McKee, A., Mesulam, M., Miller, B., Miller, C., Miller, J., Parisi, J., Perl, D., Peskind, E., Petersen, R., Poon, W., Quinn, J., Rajbhandary, R., Raskind, M., Reisberg, B., Ringman, J., Roberson, E., Rosenberg, R., Sano, M., Schneider, L., Seeley, W., Shelanski, M., Slifer, M., Smith, C., Sonnen, J., Spina, S., Stern, R., Tanzi, R., Trojanowski, J., Troncoso, J., Van Deerlin, V., Vinters, H., Vonsattel, J., Weintraub, S., Welsh-Bohmer, K., Williamson, J., Woltjer, R., Cantwell, L., Dombroski, B., Beekly, D., Lunetta, K., Martin, E., Kamboh, M., Saykin, A., Reiman, E., Bennett, D., Morris, J., Montine, T., Goate, A., Blacker, D., Tsuang, D., Hakonarson, H., Kukull, W., Foroud, T., Haines, J., Mayeux, R., Pericak-Vance, M., Farrer, L., and Schellenberg, G. (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associ-ated with late-onset Alzheimer’s disease, Nat. Genet., 43, 436–441.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Vardarajan, B., Zhang, Y., Lee, J., Cheng, R., Bohm, C., Ghani, M., Reitz, C., Reyes-Dumeyer, D., Shen, Y., Rogaeva, E., St. George-Hyslop, P., and Mayeux, R. (2015) Coding mutations in SORL1 and Alzheimer’s dis-ease, Ann. Neurol., 77, 215–27.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Bettens, K., Brouwers, N., Engelborghs, S., Lambert, J., Rogaeva. E., Vandenberghe, R., Le Bastard, N., Pasquier, F., Vermeulen, S., Van Dongen, J., Mattheijssens, M., Peeters, K., Mayeux, R., St. George-Hyslop, P., Amouyel, P., De Deyn, P., Sleegers, K., and Broeckhoven, C. (2012) Both common variations and rare non-synonymous substi-tutions and small insertion/deletions in CLU are associat-ed with increased Alzheimer’s risk, Mol. Neurodegener., 7, 3.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Narayan, P., Orte, A., Clarke, R., Bolognesi, B., Hook, S., Ganzinger, K., Meehan, S., Wilson, M., Dobson, C., and Klenerman, D. (2012) The extracellular chaperone clus-terin sequesters oligomeric forms of the amyloid-β(1-40) peptide, Nat. Struct. Mol. Biol., 19, 79–83.CrossRefGoogle Scholar
  47. 47.
    Hazrati, L., Van Cauwenberghe, C., Brooks, P., Brouwers, N., Ghani, M., Sato, C., Cruts, M., Sleegers, K., St. George-Hyslop, P., Van Broeckhoven, C., and Rogaeva, E. (2012) Genetic association of CR1 with Alzheimer’s dis-ease: a tentative disease mechanism, Neurobiol. Aging, 33, 2949.PubMedCrossRefGoogle Scholar
  48. 48.
    Jun, G., Naj, A. C., Beecham, G. W., Wang, L., Buros, J., Gallins, P., Buxbaum, J., Ertekin-Taner, N., Fallin, M., Friedland, R., Inzelberg, R., Kramer, P., Rogaeva, E., St. George-Hyslop, P., and Alzheimer’s Disease Genetics Consortium (2010) Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes, Arch. Neurol., 67, 1473–1484.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Wyss-Coray, T., Yan, F., Lin, A., Lambris, J., Alexander, J., Quigg, R., and Masliah, E. (2002) Prominent neurodegen-eration and increased plaque formation in complement-inhibited Alzheimer’s mice, Proc. Natl. Acad. Sci. USA, 99, 10837–10842.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Biffi, A., Shulman, J., Jagiella, J., Cortellini, L., Ayres, A., Schwab, K., Brown, D., Silliman, S., Selim, M., Worrall, B., Meschia, J., Slowik, A., De Jager, P., Greenberg, S., Schneider, J., Bennett, D., and Rosand, J. (2012) Genetic variation at CR1 increases risk of cerebral amyloid angiopa-thy, Neurology, 78, 334–341.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Neher, M., Rich, M., Keene, C., Weckbach, S., Bolden, A., Losacco, J., Patane, J., Flierl, M., Kulik, L., Holers, V., and Stahel, P. (2014) Deficiency of complement receptors CR2/CR1 in Cr2−/− mice reduces the extent of secondary brain damage after closed head injury, J. Neuroinflamm., 11, 95.CrossRefGoogle Scholar
  52. 52.
    Thambisetty, M., An, Y., Nalls, M., Sojkova, J., Swaminathan, S., Zhou, Y., Singleton, A., Wong, D., Ferrucci, L., Saykin, A., Resnick, S., Baltimore Longitudinal Study of Aging, and the Alzheimer’s Disease Neuroimaging Initiative (2013) The effect of CR1 on brain amyloid burden during aging and its modification by APOE genotype, Biol. Psychiatry, 73, 422–428.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hollingworth, P., Harold, D., Sims, R., Gerrish, A., Lambert, J., Carrasquillo, M., Abraham, R., Hamshere, M., Pahwa, J., Moskvina, V., Dowzell, K., Jones, N., Stretton, A., Thomas, C., Richards, A., Ivanov, D., Widdowson, C., Chapman, J., Lovestone, S., Powell, J., Proitsi, P., Lupton, M., Brayne, C., Rubinsztein, D., Gill, M., Lawlor, B., Lynch, A., Brown, K., Passmore, P., Craig, D., McGuinness, B., Todd, S., Holmes, C., Mann, D., Smith, A., Beaumont, H., Warden, D., Wilcock, G., Love, S., Kehoe, P., Hooper, N., Vardy, E., Hardy, J., Mead, S., Fox, N., Rossor, M., Collinge, J., Maier, W., Jessen, F., Ruther, E., Schurmann, B., Heun, R., Kolsch, H., Bussche, H., Heuser, I., Kornhuber, J., Wiltfang, J., Dichgans, M., Frolich, L., Hampel, H., Gallacher, J., Hull, M., Rujescu, D., Giegling, I., Goate, A., Kauwe, J., Cruchaga, C., Nowotny, P., Morris, J., Mayo, K., Sleegers, K., Bettens, K., Engelborghs, S., De Deyn, P., Broeckhoven, C., Livingston, G., Bass, N., Gurling, H., McQuillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C., Tsolaki, M., Singleton, A., Guerreiro, R., Muhleisen, T., Nothen, M., Moebus, S., Jockel, K., Klopp, N., Wichmann, H., Pankratz, V., Sando, S., Aasly, J., Barcikowska, M., Wszolek, Z., Dickson, D., Graff-Radford, N., Petersen, R., Alzheimer’s Disease Neuroimaging Initiative, and CHARGE consortium (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease, Nat. Genet., 43, 429–435.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A., Lah, J., Rujescu, D., Hampel, H., Giegling, I., Andreassen, O., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-Verbaas, C., Hofman, A., Ikram, M., Duijn, C., Thorsteinsdottir, U., Kong, A., and Stefansson, K. (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease, N. Engl. J. Med., 368, 107–116.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Benitez, B., Jin, S., Guerreiro, R., Graham, R., Lord, J., Harold, D., Sims, R., Lambert, J., Gibbs, J., Bras, J., Sassi, C., Harari, O., Bertelsen, S., Lupton, M., Powell, J., Bellenguez, C., Brown, K., Medway, C., Haddick, P., Brug, M., Bhangale, T., Ortmann, W., Behrens, T., Mayeux, R., Pericak-Vance, M., Farrer, L., Schellenberg, G., Haines, J., Turton, J., Braae, A., Barber, I., Fagan, A., Holtzman, D., Morris, J., 3C Study Group, EADI consortium, Alzheimer’s Disease Genetic Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and GERAD consortium (2014) Missense variant in TREML2 protects against Alzheimer’s disease, Neurobiol. Aging, 35, 19–26.CrossRefGoogle Scholar
  56. 56.
    Griciuc, A., Serrano-Pozo, A., Parrado, A., Lesinski, A., Asselin, C., Mullin, K., Hooli, B., Choi, S., Hyman, B., and Tanzi, R. (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta, Neuron, 78, 631–643.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kleinberger, G., Yamanishi, Y., Suarez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., Tahirovic, S., Lleo, A., Alcolea, D., Fortea, J., Willem, M., Lammich, S., Molinuevo J., Sanchez-Valle, R., Antonell, A., Ramirez, A., Heneka, M., Sleegers, K., Zee, J., Martin, J., Engelborghs, S., Demirtas-Tatlidede, A., Zetterberg, H., Broeckhoven, C., Gurvit, H., Wyss-Coray, T., Hardy, J., Colonna, M., and Haass, C. (2014) TREM2 mutations implicated in neurodegeneration impair cell surface trans-port and phagocytosis, Sci. Transl. Med., 6, 243.CrossRefGoogle Scholar
  58. 58.
    Goedert, M. (2005) Tau gene mutations and their effects, Mov. Disord., 20, 45–52.CrossRefGoogle Scholar
  59. 59.
    Nelson, P., Braak, H., and Markesbery, W. (2009) Neuropathology and cognitive impairment in Alzheimer’s disease: a complex but coherent relationship, J. Neuropathol. Exp. Neurol., 68, 1–14.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Serrano-Pozo, A., Frosch, M., Masliah, E., and Hyman, B. (2011) Neuropathological alterations in Alzheimer’s dis-ease, Cold Spring Harb. Perspect. Med., 1, a006189.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Jack, C., and Holtzman, D. (2013) Biomarker modeling of Alzheimer’s disease, Neuron, 80, 1347–1358.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lleo, A., Cavedo, E., Parnetti, L., Vanderstichele, H., Herukka, S., Andreasen, N., Ghidoni, R., Lewczuk, P., Jeromin, A., Winblad, B., Tsolaki, M., Mroczko, B., Visser, P., Santana, I., Svenningsson, P., Blennow, K., Aarsland, D., Molinuevo, J., Zetterberg, H., and Mollenhauer, B. (2015) Cerebrospinal fluid biomarkers in trials for Alzheimer’s and Parkinson’s diseases, Nat. Rev. Neurol., 11, 41–55.PubMedCrossRefGoogle Scholar
  63. 63.
    Risacher, S., and Saykin, A. (2013) Neuroimaging bio-markers of neurodegenerative diseases and dementia, Semin. Neurol., 33, 386–416.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Thal, D., Attems, J., and Ewers, M. (2014) Spreading of amyloid, tau, and microvascular pathology in Alzheimer’s disease: findings from neuropathological and neuroimaging studies, J. Alzheimer’s Dis., 42 (Suppl. 4), 421–429.Google Scholar
  65. 65.
    Wicklund, M., and Petersen, R. (2013) Emerging biomark-ers in cognition, Clin. Geriatr. Med., 29, 809–828.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Crary, J., Trojanowski, J., Schneider, J., Abisambra, J., Abner, E., Alafuzoff, I., Arnold, S., Attems, J., Beach, T., Bigio, E., Cairns, N., Dickson, D., Gearing, M., Grinberg, L., Hof, P., Hyman, B., Jellinger, K., Jicha, G., Kovacs, G., Knopman, D., Kofler, J., Kukull, W., Mackenzie, I., Masliah, E., McKee, A., Montine, T., Murray, M., Neltner, J., Santa-Maria, I., Seeley, W., Serrano-Pozo, A., Shelanski, M., Stein, T., Takao, M., Thal, D., Toledo, J., Troncoso, J., Vonsattel, J., White, C., 3rd, Wisniewski, T., Woltjer, R., Yamada, M., and Nelson, P. (2014) Primary age-related tauopathy (PART): a common pathology asso-ciated with human aging, Acta Neuropathol., 128, 755–766.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Jack, C., Wiste, H., Knopman, D., Vemuri, P., Mielke, M., Weigand, S., Senjem, M., Gunter, J., Lowe, V., Gregg, B., Pankratz, V., and Petersen, R. (2014) Rates of beta-amy-loid accumulation are independent of hippocampal neu-rodegeneration, Neurology, 82, 1605–1612.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Nussbaum, J., Seward, M., and Bloom, G. (2013) Alzheimer’s disease: a tale of two prions, Prion, 7, 14–19.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Selkoe, D. (2001) Alzheimer’s disease: genes, proteins, and therapy, Physiol. Rev., 81, 741–766.PubMedGoogle Scholar
  70. 70.
    King, M., Kan, H., Baas, P., Erisir, A., Glabe, C., and Bloom, G. (2006) Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid, J. Cell Biol., 175, 541–546.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Nath, S., Agholme, L., Kurudenkandy, F., Granseth, B., Marcusson, J., and Hallbeck, M. (2012) Spreading of neuro-degenerative pathology via neuron-to-neuron trans-mission of β-amyloid, J. Neurosci., 32, 8767–8777.PubMedCrossRefGoogle Scholar
  72. 72.
    Nussbaum, J., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Ronicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C., Demuth, H., and Bloom, G. (2012) Prion-like behavior and tau-dependent cytotoxic-ity of pyroglutamylated amyloid-β, Nature, 485, 651–655.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Picone, P., Carrotta, R., Montana, G., Nobile, M., San Biagio, P., and Di Carlo, M. (2009) Abeta oligomers and fibrillar aggregates induce different apoptotic pathways in LAN5 neuroblastoma cell cultures, Biophys. J., 96, 4200–4211.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Seward, M., Swanson, E., Roberson, E., and Bloom, G. (2012) Amyloid-β signals through tau to drive neuronal cell cycle re-entry in Alzheimer’s disease, J. Cell Sci., 126, 1278–1286.CrossRefGoogle Scholar
  75. 75.
    Westerman, M., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L., and Ashe, K. (2002) The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease, J. Neurosci., 22, 1858–1867.PubMedGoogle Scholar
  76. 76.
    Weingarten, M., Lockwood, A., Hwo, S.-Y., and Kirschner, M. (1975) A protein factor essential for microtubule assem-bly, Proc. Natl. Acad. Sci. USA, 72, 1858–1862.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Grundke-Iqbal, I., Iqbal, K., Tung, Y., Quinlan, M., Wisniewski, H., and Binder, L. (1986) Abnormal phospho-rylation of the microtubule-associated protein tau (tau) in Alzheimer’s cytoskeletal pathology, Proc. Natl. Acad. Sci. USA, 83, 4913–4917.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kondo, J., Honda, T., Mori, H., Hamada, Y., Miura, R., Ogawara, M., and Ihara, Y. (1988) The carboxyl third of tau is tightly bound to paired helical filaments, Neuron, 1, 827–834.PubMedCrossRefGoogle Scholar
  79. 79.
    Kosik, K., Orecchio, L., Binder, L., Trojanowski, J., Lee, V., and Lee, G. (1988) Epitopes that span the tau molecule are shared with paired helical filaments, Neuron, 1, 817–825.PubMedCrossRefGoogle Scholar
  80. 80.
    Stamer, K., Vogel, R., Thies, E., Mandelkow, E., and Mandelkow, E. (2002) Tau blocks traffic of organelles, neu-rofilaments, and APP vesicles in neurons and enhances oxidative stress, J. Cell Biol., 156, 1051–1063.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kolarova, M., Garcia-Sierra, F., Bartos, A., Ricny, J., and Ripova, D. (2012) Structure and pathology of tau protein in Alzheimer disease, Int. J. Alzheimer’s Dis., 2012, 731526.Google Scholar
  82. 82.
    Hanger, D., Anderton, B., and Noble, W. (2009) Tau phos-phorylation: the therapeutic challenge for neurodegenera-tive disease, Trends Mol. Med., 15, 112–119.PubMedCrossRefGoogle Scholar
  83. 83.
    Porzig, R., Singer, D., and Hoffmann, R. (2007) Epitope mapping of mAbs AT8 and Tau5 directed against hyper-phosphorylated regions of the human tau protein, Biochem. Biophys. Res. Commun., 358, 644–649.PubMedCrossRefGoogle Scholar
  84. 84.
    Klenyaeva, A., Chuprov-Netochin, R., Marusich, E., Tatarnikova, O., Orlov, M., and Bobkova, N. (2014) Development of mouse fibroblast cell line expressing human tau protein and evaluation of tau-dependent cyto-toxity, Biochemistry (Moscow), Ser. A: Membr. Cell Biol., 8, 232–239.Google Scholar
  85. 85.
    Tatarnikova, O., Klenyaeva, A., Orlov, M., Panchenko, M., Sergeev, A., and Bobkova, N. (2014) Tau-mediated toxicity of beta-amyloid, Neurocomp. Dev. Appl., 4, 55–56.Google Scholar
  86. 86.
    Beekes, M., Thomzig, A., Schulz-Schaeffer, W. J., and Burger, R. (2014) Is there a risk of prion-like disease trans-mission by Alzheimer-or Parkinson-associated protein particles? Acta Neuropathol., 128, 463–476.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Brundin, P., Melki, R., and Kopito, R. (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases, Nat. Rev. Mol. Cell Biol., 11, 301–307.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Prusiner, S. (1982) Novel proteinaceous infectious particles cause scrapie, Science, 216, 136–144.PubMedCrossRefGoogle Scholar
  89. 89.
    Prusiner, S. (1984) Some speculations about prions, amy-loid, and Alzheimer’s disease, N. Engl. J. Med., 310, 661–663.PubMedCrossRefGoogle Scholar
  90. 90.
    Frost, B., and Diamond, M. (2010) Prion-like mecha-nisms in neurodegenerative diseases, Nat. Rev. Neurosci., 11, 155–159.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Goedert, M., Clavaguera, F., and Tolnay, M. (2010) The propagation of prion-like protein inclusions in neurode-generative diseases, Trends Neurosci., 33, 317–325.PubMedCrossRefGoogle Scholar
  92. 92.
    Lee, S., Desplats, P., Sigurdson, C., Tsigelny, I., and Masliah, E. (2010) Cell-to-cell transmission of nonprion protein aggregates, Nat. Rev. Neurol., 6, 702–706.PubMedCrossRefGoogle Scholar
  93. 93.
    Novak, P., Prcina, M., and Kontsekova, E. (2011) Tauons and prions: infamous cousins? J. Alzheimer’s Dis., 26, 413–430.CrossRefGoogle Scholar
  94. 94.
    Prusiner, S. (2012) Cell biology. A unifying role for prions in neurodegenerative diseases, Science, 336, 1511–1513.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Harris, J., Devidze, N., Verret, L., Ho, K., Halabisky, B., Thwin, M., Kim, D., Hamto, P., Lo, I., Yu, G., Palop, J., Masliah, E., and Mucke, L. (2010) Transsynaptic progres-sion of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network, Neuron, 68, 428–441.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Braak, H., and Del Tredici, K. (2011) Alzheimer’s patho-genesis: is there neuron-to-neuron propagation? Acta Neuropathol., 121, 589–595.PubMedCrossRefGoogle Scholar
  97. 97.
    Clavaguera, F., Bolmont, T., Crowther, R., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., and Tolnay, M. (2009) Transmission and spreading of tauopathy in transgenic mouse brain, Nat. Cell Biol., 11, 909–913.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    De Calignon, A., Polydoro, M., Suarez-Calvet, M., William, C., Adamowicz, D., Kopeikina, K., Pitstick, R., Sahara, N., Ashe, K., Carlson, G., Spires-Jones, T., and Hyman, B. (2012) Propagation of tau pathology in a model of early Alzheimer’s disease, Neuron, 73, 685–697.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Guo, J., and Lee, V. (2011) Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles, J. Biol. Chem., 286, 15317–15331.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Liu, L., Drouet, V., Wu, J., Witter, M., Small, S., Clelland, C., and Duff, K. (2012) Trans-synaptic spread of tau pathology in vivo, PLoS One, 7, e31302.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Nussbaum, J., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Ronicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C., Demuth, H., and Bloom, G. (2012) Prion-like behavior and tau-dependent cytotoxicity of pyroglutamylated amyloid-β, Nature, 485, 651–655.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Hurtado, D., Molina-Porcel, L., Iba, M., Aboagye, A., Paul, S., Trojanowski, J., and Lee, V. (2010) Abeta accel-erates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer’s mouse model, Am. J. Pathol., 177, 1977–1988.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Miller, Y., Ma, B., and Nussinov, R. (2011) Synergistic interactions between repeats in tau protein and Aβ amy-loids may be responsible for accelerated aggregation via polymorphic states, Biochemistry, 50, 5172–5181.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Pauwels, K., Williams, T., Morris, K., Jonckheere, W., Vandersteen, A., Kelly, G., Schymkowitz, J., Rousseau, F., Pastore, A., Serpell, L., and Broersen, K. (2012) Structural basis for increased toxicity of pathological aβ42/aβ40 ratios in Alzheimer’s disease, J. Biol. Chem., 287, 5650–5660.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Stohr, J., Watts, J., Mensinger, Z., Oehler, A., Grillo, S., DeArmond, S., Prusiner S., and Giles, K. (2012) Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions, Proc. Natl. Acad. Sci. USA, 109, 11025–11030.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Jucker, M., and Walker, L. (2011) Pathogenic protein seeding in Alzheimer’s disease and other neurodegenera-tive disorders, Ann. Neurol., 70, 532–740.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Guo, J., Arai, T., Miklossy, J., and McGeer, P. (2006) Abeta and tau form soluble complexes that may promote self-aggregation of both into the insoluble forms observed in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 103, 1953–1958.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Lasagna-Reeves, C., Castillo-Carranza, D., Guerrero-Muoz, M., Jackson, G., and Kayed, R. (2010) Preparation and characterization of neurotoxic tau oligomers, Biochemistry, 49, 10039–10041.PubMedCrossRefGoogle Scholar
  109. 109.
    Gotz, J., Chen, F., Van Dorpe, J., and Nitsch, R. (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science, 293, 1491–1495.PubMedCrossRefGoogle Scholar
  110. 110.
    Lewis, J., Dickson, D., Lin, W.-L., Chisholm, L., Corral, A., Jones, G., Yen, S., Sahara, N., Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., and McGowan, E. (2001) Enhanced neurofibrillary degeneration in trans-genic mice expressing mutant tau and APP, Science, 293, 1487–1491.PubMedCrossRefGoogle Scholar
  111. 111.
    Rapoport, M., Dawson, H., Binder, L., Vitek, M., and Ferreira, A. (2002) Tau is essential to β-amyloid-induced neurotoxicity, Proc. Natl. Acad. Sci. USA, 99, 6364–6369.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Roberson, E., Scearce-Levie, K., Palop, J., Yan, F., Cheng, I., Wu, T., Gerstein, H., Yu, G., and Mucke, L. (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model, Science, 316, 750–754.PubMedCrossRefGoogle Scholar
  113. 113.
    Seino, Y., Kawarabayashi, T., Wakasaya, Y., Watanabe, M., Takamura, A., Yamamoto-Watanabe, Y., Kurata, T., Abe, K., Ikeda, M., Westaway, D., Murakami, T., Hyslop, P., Matsubara, E., and Shoji, M. (2010) Amyloid β acceler-ates phosphorylation of tau and neurofibrillary tangle for-mation in an amyloid precursor protein and tau double-transgenic mouse model, J. Neurosci. Res., 88, 3547–3554.PubMedCrossRefGoogle Scholar
  114. 114.
    Zempel, H., Thies, E., Mandelkow, E., and Mandelkow, E. (2010) Abeta oligomers cause localized Ca(2+) eleva-tion, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines, J. Neurosci., 30, 11938–11950.PubMedCrossRefGoogle Scholar
  115. 115.
    Eisele, Y., Obermuller, U., Heilbronner, G., Baumann, F., Kaeser, S., Wolburg, H., Walker, L., Staufenbiel, M., Heikenwalder, M., and Jucker, M. (2010) Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis, Science, 330, 980–982.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., Neuenschwander, A., Abramowski, D., Frey, P., Jaton, A., Vigouret, J., Paganetti, P., Walsh, D., Mathews, P., Ghiso, J., Staufenbiel, M., Walker, L., and Jucker, M. (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host, Science, 313, 1781–1784.PubMedCrossRefGoogle Scholar
  117. 117.
    Walker, L., Callahan, M., Bian, F., Durham, R., Roher, A., and Lipinski, W. (2002) Exogenous induction of cere-bral beta-amyloidosis in betaAPP-transgenic mice, Peptides, 23, 1241–1247.PubMedCrossRefGoogle Scholar
  118. 118.
    Kayed, R., Canto, I., Breydo, L., Rasool, S., Lukacsovich, T., Wu, J., Albay, R., 3rd, Pensalfini, A., Yeung, S., Head, E., Marsh, J., and Glabe, C. (2010) Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers, Mol. Neurodegener., 5, 57.Google Scholar
  119. 119.
    Davis, R., Marsden, I., Maloney, M., Minamide, L., Podlisny, M., Selkoe, D., and Bamburg, J. (2011) Amyloid beta dimers/trimers potently induce cofilin−actin rods that are inhibited by maintaining cofilin-phosphorylation, Mol. Neurodegener., 6, 10.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Shankar, G., Bloodgood, B., Townsend, M., Walsh, D., Selkoe, D., and Sabatini, B. (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway, J. Neurosci., 27, 2866–2875.PubMedCrossRefGoogle Scholar
  121. 121.
    Shankar, G., Li, S., Mehta, T., Garcia-Munoz, A., Shepardson, N., Smith, I., Brett, F., Farrell, M., Rowan, M., Lemere, C., Regan, C., Walsh, D., Sabatini, B., and Selkoe, D. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat. Med., 14, 837–842.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Portelius, E., Westman-Brinkmalm, A., Zetterberg, H., and Blennow, K. (2006) Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immuno-precipitation-mass spectrometry, J. Proteome. Res., 5, 1010–1016.PubMedCrossRefGoogle Scholar
  123. 123.
    Jeganathan, S., Von Bergen, M., Mandelkow, E.-M., and Mandelkow, E. (2008) The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical fil-aments, Biochemistry, 47, 10526–10539.PubMedCrossRefGoogle Scholar
  124. 124.
    Gamblin, T., King, M., Dawson, H., Vitek, M., Kuret, J., Berry, R., and Binder, L. (2000) In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants, Biochemistry, 39, 6136–6144.PubMedCrossRefGoogle Scholar
  125. 125.
    Patterson, K., Remmers, C., Fu, Y., Brooker, S., Kanaan, N., Vana, L., Ward, S., Reyes, J., Philibert, K., Glucksman, M., and Binder, L. (2011) Characterization of prefibrillar Tau oligomers in vitro and in Alzheimer’s dis-ease, J. Biol. Chem., 286, 23063–23076.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Friedhoff, P., Von Bergen, M., Mandelkow, E., Davies, P., and Mandelkow, E. (1998) A nucleated assembly mecha-nism of Alzheimer paired helical filaments, Proc. Natl. Acad. Sci. USA, 95, 15712–15717.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Frost, B., Jacks, R., and Diamond, M. (2009) Propagation of tau misfolding from the outside to the inside of a cell, J. Biol. Chem., 284, 12845–12852.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Nonaka, T., Watanabe, S., Iwatsubo, T., and Hasegawa, M. (2010) Seeded aggregation and toxicity of alpha-synuclein and tau: cellular models of neurodegenerative diseases, J. Biol. Chem., 285, 34885–34898.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Lasagna-Reeves, C., Castillo-Carranza, D., Sengupta, U., Sarmiento, J., Troncoso, J., Jackson, G., and Kayed, R. (2012) Identification of oligomers at early stages of tau aggre-gation in Alzheimer’s disease, FASEB J., 26, 1946–1959.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Lasagna-Reeves, C., Castillo-Carranza, D., Sengupta, U., Clos, A., Jackson, G., and Kayed, R. (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice, Mol. Neurodegener., 6, 39.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Ittner, L., Ke, Y., Delerue, F., Bi, M., Gladbach, A., Van Eersel, J., Wolfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., Eckert, A., Staufenbiel, M., Hardeman, E., and Gotz, J. (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse mod-els, Cell, 142, 387–397.PubMedCrossRefGoogle Scholar
  132. 132.
    Vossel, K., Zhang, K., Brodbeck, J., Daub, A., Sharma, P., Finkbeiner, S., Cui, B., and Mucke, L. (2010) Tau reduc-tion prevents Abeta-induced defects in axonal transport, Science, 330, 198.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Rhinn, H., Fujita, R., Qiang, L., Cheng, R., Lee, J., and Abeliovich, A. (2013) Integrative genomics identifies APOE epsilon 4 effectors in Alzheimer’s disease, Nature, 500, 45–50.PubMedCrossRefGoogle Scholar
  134. 134.
    Santiago, J., and Potashkin, J. (2014) A network approach to clinical intervention in neurodegenerative diseases, Trends Mol. Med., 20, 694–703.PubMedCrossRefGoogle Scholar
  135. 135.
    Zhang, B., Gaiteri, C., Bodea, L., Wang, Z., McElwee, J., Podtelezhnikov, A., Zhang, C., Xie, T., Tran, L., Dobrin, R., Fluder, E., Clurman, B., Melquist, S., Narayanan, M., Suver, C., Shah, H., Mahajan, M., Gillis, T., Mysore, J., MacDonald, M. E., Lamb, J. R., Bennett, D. A., Molony, C., Stone, D. J., Gudnason, V., Myers, A. J., Schadt, E. E., Neumann, H., Zhu, J., and Emilsson, V. (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease, Cell, 153, 707–720.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Hampel, H., Schneider, L., Giacobini, E., Kivipelto, M., Sindi, S., Dubois, B., Broich, K., Nistico, R., Aisen, P., and Lista, S. (2014) Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future, Exp. Rev. Neurother., 15, 83–105.CrossRefGoogle Scholar
  137. 137.
    Huang, Y., and Mucke, L. (2012) Alzheimer mechanisms and therapeutic strategies, Cell, 148, 1204–1222.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Narayan, P., Ehsani, S., and Lindquist, S. (2014) Combating neurodegenerative disease with chemical probes and model systems, Nat. Chem. Biol., 10, 911–920.PubMedCrossRefGoogle Scholar
  139. 139.
    Pimenova, A., Thathiah, A., De Strooper, B., and Tesseur, I. (2014) Regulation of amyloid precursor protein process-ing by serotonin signaling, PLoS One, 9, e87014.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Fragkouli, A., Tsilibary, E., and Tzinia, A. (2014) Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer’s 5xFAD mice, Neurobiol. Dis., 70, 179–189.PubMedCrossRefGoogle Scholar
  141. 141.
    Shukla, M., Htoo, H., Wintachai, P., Hernandez, J., Dubois, C., Postina, R., Xu, H., Checler, F., Smith, D., Govitrapong, P., and Vincent, B. (2015) Melatonin stimu-lates the nonamyloidogenic processing of betaAPP through the positive transcriptional regulation of ADAM10 and ADAM17, J. Pineal Res., 58, 151–165.PubMedCrossRefGoogle Scholar
  142. 142.
    Willem, M., Garratt, A., Novak, B., Citron, M., Kaufmann, S., Rittger, A., DeStrooper, B., Saftig, P., Birchmeier, C., and Haass, C. (2006) Control of peripher-al nerve myelination by the β-secretase BACE1, Science, 314, 664–666.PubMedCrossRefGoogle Scholar
  143. 143.
    Kim, D., Carey, B., Wang, H., Ingano, L., Binshtok, A., Wertz, M., Pettingell, W., He, Lee, V., Woolf, C., and Kovacs, D. (2007) BACE1 regulates voltage-gated sodium channels and neuronal activity, Nat. Cell Biol., 9, 755–764.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Butini, S., Brogi, S., Novellino, E., Campiani, G., Ghosh, A., Brindisi, M., and Gemma, S. (2013) The structural evolution of beta-secretase inhibitors: a focus on the devel-opment of small-molecule inhibitors, Curr. Top. Med. Chem., 13, 1787–1807.PubMedCrossRefGoogle Scholar
  145. 145.
    Vassar, R., Kuhn, P.-H., Haass, C., Kennedy, M., Rajendran, L., Wong, P., and Lichtenthaler, S. (2014) Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects, J. Neurochem., 130, 4–28.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Cummings, J. (2010) What can be inferred from the inter-ruption of the semagacestat trial for treatment of Alzheimer’s disease? Biol. Psychiatry, 68, 876–878.PubMedCrossRefGoogle Scholar
  147. 147.
    Doody, R., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R., Aisen, P., Siemers, E., Sethuraman, G., Mohs, R., and Semagacestat Study Group (2013) A phase 3 trial of sema-gacestat for treatment of Alzheimer’s disease, N. Engl. J. Med., 369, 341–350.PubMedCrossRefGoogle Scholar
  148. 148.
    Golde, T., Koo, E., Felsenstein, K., Osborne, B., and Miele, L. (2013) γ-Secretase inhibitors and modulators, Biochim. Biophys. Acta, 1828, 2898–2907.PubMedCrossRefGoogle Scholar
  149. 149.
    Hall, A., and Patel, T. R. (2014) Gamma-secretase modu-lators: current status and future directions, Prog. Med. Chem., 53, 101–145.PubMedCrossRefGoogle Scholar
  150. 150.
    Pettersson, M., Stepan, A., Kauffman, G., and Johnson, D. (2013) Novel gamma-secretase modulators for the treatment of Alzheimer’s disease: a review focusing on patents from 2010 to 2012, Expert Opin. Ther. Pat., 23, 1349–1366.PubMedCrossRefGoogle Scholar
  151. 151.
    Crump, C., Johnson, D., and Li, Y.-M. (2013) Development and mechanism of γ-secretase modulators for Alzheimer’s disease, Biochemistry, 52, 3197–3216.PubMedCrossRefGoogle Scholar
  152. 152.
    Takeo, K., Tanimura, S., Shinoda, T., Osawa, S., Zahariev, I., Takegami, N., Ishizuka-Katsura, Y., Shinya, N., Takagi-Niidome, S., Tominaga, A., Ohsawa, N., Kimura-Someya, T., Shirouzu, M., Yokoshima, S., Yokoyama, S., Fukuyama, T., Tomita, T., and Iwatsubo, T. (2014) Allosteric regulation of γ-secretase activity by a phenylim-idazole-type γ-secretase modulator, Proc. Natl. Acad. Sci. USA, 111, 10544–10549.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Mecozzi, V., Berman, D., Simoes, S., Vetanovetz, C., Awal, M., Patel, V., Schneider, R., Petsko, G., Ringe, D., and Small, S. (2014) Pharmacological chaperones stabilize retromer to limit APP processing, Nat. Chem. Biol., 10, 443–449.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    McLaurin, J., Kierstead, M., Brown, M., Hawkes, C., Lambermon, M., Phinney, A., Darabie, A., Cousins, J., French, J., Lan, M., Chen, F., Wong, S., Mount, H., Fraser, P., Westaway, D., and St. George-Hyslop, P. (2006) Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model, Nat. Med., 12, 801–808.PubMedCrossRefGoogle Scholar
  155. 155.
    Salloway, S., Sperling, R., Keren, R., Porsteinsson, A., Van Dyck, C., Tariot, P., Gilman, S., Arnold, D., Abushakra, S., Hernandez, C., Crans, G., Liang, E., Quinn, G., Bairu, M., Pastrak, A., Cedarbaum, J., and ELND005-AD201 Investigators (2011) A phase 2 ran-domized trial of ELND005, scylloinositol, in mild to moderate Alzheimer’s disease, Neurology, 77, 1253–1262.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Bobkova, N., Lyabin, D., Medvinskaya, N., Samokhin, A., Nekrasov, P., Nesterova, I., Aleksandrova, I., Tatarnikova, O., Bobylev, A., Vikhlyantsev, I., Kukharsky, M., Ustyugov, A., Polyakov, D., Eliseeva, I., Kretov, D., Guryanov, S., and Ovchinnikov, L. (2015) The Y-box binding protein 1 suppresses Alzheimer’s disease pro-gression in two animal models, PLoS One, 10, e0138867.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Saito, S., and Ihara, M. (2014) New therapeutic approaches for Alzheimer’s disease and cerebral amyloid angiopathy, Front. Aging Neurosci., 6, 290.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Miners, J., Palmer, J., Tayler, H., Palmer, L., Ashby, E., Kehoe, P., and Love, S. (2014) Abeta degradation or cere-bral perfusion? Divergent effects of multifunctional enzymes, Front. Aging Neurosci., 6, 238.PubMedGoogle Scholar
  159. 159.
    Ibrahim, Z., Armour, C., Phipps, S., and Sukkar, M. (2013) RAGE and TLRs: relatives, friends or neighbors? Mol. Immunol., 56, 739–744.PubMedCrossRefGoogle Scholar
  160. 160.
    Deane, R., Du Yan, S., Submamaryan, R., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A., Armstrong, D., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M., Stern, D., and Zlokovic, B. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain, Nat. Med., 9, 907–913.PubMedCrossRefGoogle Scholar
  161. 161.
    Volpina, O., Koroev, D., Volkova, T., Kamynina, A., Filatova, A., Zaporozhskaya, Y., Samokhin, A., and Bobkova, N. (2015) Fragment of the receptor for advanced glycation end products recovery of spatial mem-ory of animals in Alzheimer’s disease model, Bioorg. Chem., in press.Google Scholar
  162. 162.
    Holtzman, D., Herz, J., and Bu, G. (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer’s disease, Cold Spring Harb. Perspect. Med., 2, a006312.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Sagare, A., Bell, R., Srivastava, A., Sengillo, J., Singh, I., Nishida, Y., Chow, N., and Zlokovic, B. (2013) A lipopro-tein receptor cluster IV mutant preferentially binds amy-loid-β and regulates its clearance from the mouse brain, J. Biol. Chem., 288, 15154–15166.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Verghese, P., Castellano, J., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., and Holtzman, D. (2013) ApoE influences amyloid-β (Aβ) clearance despite mini-mal apoE/Aβ association in physiological conditions, Proc. Natl. Acad. Sci. USA, 110, 1807–1816.CrossRefGoogle Scholar
  165. 165.
    Laffitte, B., Repa, J., Joseph, S., Wilpitz, D., Kast, H., Mangelsdorf, D., and Tontonoz, P. (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes, Proc. Natl. Acad. Sci. USA, 98, 507–512.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Cramer, P., Cirrito, J., Wesson, D., Lee, C., Karlo, J., Zinn, A., Casali, B., Restivo, J., Goebel, W., James, M., Brunden, K., Wilson, D., and Landreth, G. (2012) ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models, Science, 335, 1503–1506.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Price, A., Xu, G., Siemienski, Z., Smithson, L., Borchelt, D., Golde, T., and Felsenstein, K. (2013) Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”, Science, 340, 924–924.PubMedCrossRefGoogle Scholar
  168. 168.
    Tesseur, I., Lo, A., Roberfroid, A., Dietvorst, S., Broeck, B., Borgers, M., Gijsen, H., Moechars, D., Mercken, M., Kemp, J., D’Hooge, R., and De Strooper, B. (2013) Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”, Science, 340, 924–924.PubMedCrossRefGoogle Scholar
  169. 169.
    Veeraraghavalu, K., Zhang, C., Miller, S., Hefendehl, J., Rajapaksha, T., Ulrich, J., Jucker, M., Holtzman, D., Tanzi, R., Vassar, R., and Sisodia, S. (2013) Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”, Science, 340, 924–924.PubMedCrossRefGoogle Scholar
  170. 170.
    Kamynina, A., Volpina, O., Medvinskaya, N., Aleksandrova, I., Volkova, T., Koroev, D., Samokhin, A., Nesterova, I., Shelukhina, I., Kryukova, E., Tsetlin, V., Ivanov, V., and Bobkova, N. (2010) Vaccination with pep-tide 173-193 of acetylcholine receptor α7-subunit prevents memory loss in olfactory bulbectomized mice, J. Alzheimer’s Dis., 21, 249–261.Google Scholar
  171. 171.
    Bobkova, N., Medvinskaya, N., Kamynina, A., Aleksandrova, I., Nesterova, I., Samokhin, A., Koroev, D., Filatova, M., Nekrasov, P., Abramov, A., Leonov, S., and Volpina, O. (2014) Immunization with either prion protein fragment 95-123 or the fragment-specific antibodies res-cue memory loss and neurodegenerative phenotype of neurons in olfactory bulbectomized mice, Neurobiol. Learn. Mem., 107, 50–64.PubMedCrossRefGoogle Scholar
  172. 172.
    Volpina, O., Medvinskava, N., Kamynina, A., Zaporozhskaia, Ia., Aleksandrova, I., Koroev, D., Samokhin, A., Volkova, T., Arsenev, A., and Bobkova, N. (2014) Immunization with a synthetic fragment 155-164 of neurotrophin receptor p75 prevents memory loss and decreases beta-amyloid level in mice with experimentally induced Alzheimer’s disease, Bioorg. Khim., 40, 451–457.Google Scholar
  173. 173.
    Janus, C., Pearson, J., McLaurin, J., Mathews, P., Jiang, Y., Schmidt, S., Chishti, M., Horne, P., Heslin, D., French, J., Mount, H., Nixon, R., Mercken, M., Bergeron, C., Fraser, P., St. George-Hyslop, P., and Westaway, D. (2000) Abeta peptide immunization reduces behavioral impairment and plaques in a model of Alzheimer’s disease, Nature, 408, 979–982.PubMedCrossRefGoogle Scholar
  174. 174.
    Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg, I., Motter, R., Mutter, L., Soriano, F., Shopp, G., Vasquez, N., Vandevert, C., Walker, S., Wogulis, M., Yednock, T., Games, D., and Seubert, P. (1999) Immunization with amyloid-beta attenuates Alzheimer’s-disease-like patholo-gy in the PDAPP mouse, Nature, 400, 173–177.PubMedCrossRefGoogle Scholar
  175. 175.
    Orgogozo, J., Gilman, S., Dartigues, J., Laurent, B., Puel, M., Kirby, L., Jouanny, P., Dubois, B., Eisner, L., Flitman, S., Michel, B., Boada, M., Frank, A., and Hock, C. (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization, Neurology, 61, 46–54.PubMedCrossRefGoogle Scholar
  176. 176.
    Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R., Bullock, R., Love, S., Neal, J., Zotova, E., and Nicoll, J. (2008) Long-term effects of Abeta42 immunization in Alzheimer’s disease: follow-up of a randomized, placebo-controlled phase I trial, Lancet, 372, 216–223.PubMedCrossRefGoogle Scholar
  177. 177.
    St. George-Hyslop, P., and Morris, J. (2008) Will anti-amyloid therapies work for Alzheimer’s disease? Lancet, 372, 180–182.CrossRefGoogle Scholar
  178. 178.
    Ostrowitzki, S., Deptula, D., Thurfjell, L., Barkhof, F., Bohrmann, B., Brooks, D. J., Klunk, W. E., Ashford, E., Yoo, K., Xu, Z.-X., Loetscher, H., and Santarelli, L. (2012) Mechanism of amyloid removal in patients with Alzheimer’s disease treated with gantenerumab, Arch. Neurol., 69, 198–207.PubMedCrossRefGoogle Scholar
  179. 179.
    Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., Siemers, E., Liu-Seifert, H., Mohs, R., Alzheimer’s Disease Cooperative Study Steering Committee, and Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease, N. Engl. J. Med., 370, 311–321.PubMedCrossRefGoogle Scholar
  180. 180.
    Spencer, B., and Masliah, E. (2014) Immunotherapy for Alzheimer’s disease: past, present and future, Front. Aging Neurosci., 6, 114.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Bateman, R., Xiong, C., Benzinger, T., Fagan, A., Goate, A., Fox, N., Marcus, D., Cairns, N., Xie, X., Blazey, T., Holtzman, D., Santacruz, A., Buckles, V., Oliver, A., Moulder, K., Aisen, P., Ghetti, B., Klunk, W., McDade, E., Martins, R., Masters, C., Mayeux, R., Ringman, J., Rossor, M., Schofield, P., Sperling, R., Salloway, S., Morris, J., and Dominantly Inherited Alzheimer’s Network (2012) Clinical and biomarker changes in domi-nantly inherited Alzheimer’s disease, N. Engl. J. Med., 367, 795–804.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Lippa, C., Nee, L., Mori, H., and St. George-Hyslop, P. (1998) Abeta-42 deposition precedes other changes in PS-1 Alzheimer’s disease, Lancet, 352, 1117–1118.PubMedCrossRefGoogle Scholar
  183. 183.
    Gong, C., Grundke-Iqbal, I., and Iqbal, K. (2010) Targeting tau protein in Alzheimer’s disease, Drugs Aging, 27, 351–365.PubMedCrossRefGoogle Scholar
  184. 184.
    Navarrete, L., Perez, P., Morales, I., and Maccioni, R. (2011) Novel drugs affecting tau behavior in the treatment of Alzheimer’s disease and tauopathies, Curr. Alzheimer’s Res., 8, 678–685.CrossRefGoogle Scholar
  185. 185.
    Taniguchi, T., Kawamata, T., Mukai, H., Hasegawa, H., Isagawa, T., Yasuda, M., Hashimoto, T., Terashima, A., Nakai, M., Mori, H., Ono, Y., and Tanaka, C. (2001) Phosphorylation of tau is regulated by PKN, J. Biol. Chem., 276, 10025–10031.PubMedCrossRefGoogle Scholar
  186. 186.
    Bandyopadhyay, B., Li, G., Yin, H., and Kuret, J. (2007) Tau aggregation and toxicity in a cell culture model of tauopathy, J. Biol. Chem., 282, 16454–16464.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2015

Authors and Affiliations

  • O. G. Tatarnikova
    • 1
    • 2
    Email author
  • M. A. Orlov
    • 1
  • N. V. Bobkova
    • 1
  1. 1.Institute of Cell BiophysicsRussian Academy of SciencesPushchino, Moscow RegionRussia
  2. 2.Pushchino State Natural Research InstitutePushchino, Moscow RegionRussia

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