Contemporary Approaches to Alzheimer’s Disease and Frontotemporal Dementia

  • Erik D. Roberson
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 670)

Abstract

Alzheimer’s disease and frontotemporal dementia are two of the most common neurodegenerative dementias. Here, we review the clinical presentation, genetic causes, typical neuropathology, and current treatments for these disorders. We then review molecules involved in their pathogenesis and protocols for working with these species and conclude with a discussion of experimental systems and outcome measures for studying these disorders.

Key words

Dementia Mild cognitive impairment Memory Personality change Disinhibition Aging Methods Protocols Aβ β-Amyloid Tau Apolipoprotein E Progranulin TDP-43 

References

  1. 1.
    Ferri, C. P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., Ganguli, M., Hall, K., Hasegawa, K., Hendrie, H., Huang, Y., Jorm, A., Mathers, C., Menezes, P. R., Rimmer, E., and Scazufca, M. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Roberson, E. D., Hesse, J. H., Rose, K. D., Slama, H., Johnson, J. K., Yaffe, K., Forman, M. S., Miller, C. A., Trojanowski, J. Q., Kramer, J. H., and Miller, B. L. (2005) Frontotemporal dementia progresses to death faster than Alzheimer disease. Neurology 65, 719–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rossor, M., Owen, M., and Hardy, J. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C. E., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., and Tanzi, R. E. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–77.PubMedCrossRefGoogle Scholar
  5. 5.
    Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Piacentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., and St George-Hyslop, P. H. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–78.PubMedCrossRefGoogle Scholar
  6. 6.
    Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., Tsuda, T., Mar, L., Foncin, J.-F., Bruni, A. C., Montesi, M. P., Sorbi, S., Rainero, I., Pinessi, L., Nee, L., Chumakov, I., Pollen, D., Brookes, A., Sanseau, P., Polinsky, R. J., Wasco, W., Da Silva, H. A. R., Haines, J. L., Pericak-Vance, M. A., Tanzi, R. E., Roses, A. D., Fraser, P. E., Rommens, J. M., and St George-Hyslop, P. H. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–60.PubMedCrossRefGoogle Scholar
  7. 7.
    De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., and Van Leuven, F. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Edbauer, D., Winkler, E., Regula, J. T., Pesold, B., Steiner, H., and Haass, C. (2003) Reconstitution of g-secretase activity. Nat. Cell Biol. 5, 486–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Farlow, M. R., Miller, M. L., and Pejovic, V. (2008) Treatment options in Alzheimer’s disease: maximizing benefit, managing expectations. Dement. Geriatr. Cogn. Disord. 25, 408–22.PubMedCrossRefGoogle Scholar
  10. 10.
    Roberson, E. D., and Mucke, L. (2006) 100 years and counting: prospects for defeating Alzheimer’s disease. Science 314, 781–84.PubMedCrossRefGoogle Scholar
  11. 11.
    Roberson, E. D. (2006) Frontotemporal dementia. Curr. Neurol. Neurosci. Rep. 6, 481–89.PubMedCrossRefGoogle Scholar
  12. 12.
    Josephs, K. A. (2008) Frontotemporal dementia and related disorders: deciphering the enigma. Ann. Neurol. 64, 4–14.PubMedCrossRefGoogle Scholar
  13. 13.
    Kertesz, A. (2009) Clinical features and diagnosis of frontotemporal dementia. Front. Neurol. Neurosci. 24, 140–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Rascovsky, K., Hodges, J. R., Kipps, C. M., Johnson, J. K., Seeley, W. W., Mendez, M. F., Knopman, D., Kertesz, A., Mesulam, M., Salmon, D. P., Galasko, D., Chow, T. W., Decarli, C., Hillis, A., Josephs, K., Kramer, J. H., Weintraub, S., Grossman, M., Gorno-Tempini, M. L., and Miller, B. M. (2007) Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis. Assoc. Disord. 21, S14–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Hodges, J. R., and Patterson, K. (2007) Semantic dementia: a unique clinicopathological syndrome. Lancet Neurol. 6, 1004–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Ogar, J. M., Dronkers, N. F., Brambati, S. M., Miller, B. L., and Gorno-Tempini, M. L. (2007) Progressive nonfluent aphasia and its characteristic motor speech deficits. Alzheimer Dis. Assoc. Disord. 21, S23–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Lillo, P., and Hodges, J. R. (2009) Fronto­temporal dementia and motor neurone disease: overlapping clinic-pathological disorders. J. Clin. Neurosci. 16, 1131–35.PubMedCrossRefGoogle Scholar
  18. 18.
    Neumann, M., Tolnay, M., and Mackenzie, I. R. (2009) The molecular basis of frontotemporal dementia. Expert Rev. Mol. Med. 11, e23.PubMedCrossRefGoogle Scholar
  19. 19.
    Neumann, M., Rademakers, R., Roeber, S., Baker, M., Kretzschmar, H. A., and Mackenzie, I. R. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–31.PubMedCrossRefGoogle Scholar
  20. 20.
    Seelaar, H., Kamphorst, W., Rosso, S. M., Azmani, A., Masdjedi, R., de Koning, I., Maat-Kievit, J. A., Anar, B., Kaat, L. D., Breedveld, G. J., Dooijes, D., Rozemuller, J. M., Bronner, I. F., Rizzu, P., and van Swieten, J. C. (2008) Distinct genetic forms of frontotemporal dementia. Neurology 71, 1220–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., Hackett, J., Adamson, J., Lincoln, S., Dickson, D., Davies, P., Petersen, R. C., Stevens, M., De Graaff, E., Wauters, E., Van Baren, J., Hillebrand, M., Joosse, M., Kwon, J. M., and Nowotny, P. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Poorkaj, P., Bird, T. D., Wijsman, E., Nemens, E., Garruto, R. M., Anderson, L., Andreadis, A., Wiederholt, W. C., Raskind, M., and Schellenberg, G. D. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–25.PubMedCrossRefGoogle Scholar
  23. 23.
    Spillantini, M. G., Murrell, J. R., Goedert, M., Farlow, M. R., Klug, A., and Ghetti, B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. U.S.A. 95, 7737–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Clark, L. N., Poorkaj, P., Wszolek, Z., Geschwind, D. H., Nasreddine, Z. S., Miller, B., Li, D., Payami, H., Awert, F., Markopoulou, K., Andreadis, A., D’Souza, I., Lee, V. M. Y., Reed, L., Trojanowski, J. Q., Zhukareva, V., Bird, T., Schellenberg, G., and Wilhelmsen, K. C. (1998) Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl. Acad. Sci. U.S.A. 95, 13103–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., Cannon, A., Dwosh, E., Neary, D., Melquist, S., Richardson, A., Dickson, D., Berger, Z., Eriksen, J., Robinson, T., Zehr, C., Dickey, C. A., Crook, R., McGowan, E., Mann, D., Boeve, B., Feldman, H., and Hutton, M. (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J. J., van Duijn, C., Peeters, K., Sciot, R., Santens, P., De Pooter, T., Mattheijssens, M., Van den Broeck, M., Cuijt, I., Vennekens, K., De Deyn, P. P., Kumar-Singh, S., and Van Broeckhoven, C. (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–24.PubMedCrossRefGoogle Scholar
  27. 27.
    Gass, J., Cannon, A., Mackenzie, I. R., Boeve, B., Baker, M., Adamson, J., Crook, R., Melquist, S., Kuntz, K., Petersen, R., Josephs, K., Pickering-Brown, S. M., Graff-Radford, N., Uitti, R., Dickson, D., Wszolek, Z., Gonzalez, J., Beach, T. G., Bigio, E., Johnson, N., Weintraub, S., Mesulam, M., White, C. L., 3rd, Woodruff, B., Caselli, R., Hsiung, G. Y., Feldman, H., Knopman, D., Hutton, M., and Rademakers, R. (2006) Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum. Mol. Genet. 15, 2988–3001.PubMedCrossRefGoogle Scholar
  28. 28.
    Mackenzie, I. R. (2007) The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol. 114, 49–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H., Nielsen, J. E., Hodges, J. R., Spillantini, M. G., Thusgaard, T., Brandner, S., Brun, A., Rossor, M. N., Gade, A., Johannsen, P., Sorensen, S. A., Gydesen, S., Fisher, E. M., and Collinge, J. (2005) Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Urwin, H., Ghazi-Noori, S., Collinge, J., and Isaacs, A. (2009) The role of CHMP2B in frontotemporal dementia. Biochem. Soc. Trans. 37, 208–12.PubMedCrossRefGoogle Scholar
  31. 31.
    Watts, G. D., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., and Kimonis, V. E. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Kimonis, V. E., Fulchiero, E., Vesa, J., and Watts, G. (2008) VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. Biochim. Biophys. Acta 1782, 744–48.PubMedCrossRefGoogle Scholar
  33. 33.
    Vossel, K. A., and Miller, B. L. (2008) New approaches to the treatment of frontotemporal lobar degeneration. Curr. Opin. Neurol. 21, 708–16.PubMedCrossRefGoogle Scholar
  34. 34.
    Mendez, M. F. (2009) Frontotemporal dementia: therapeutic interventions. Front. Neurol. Neurosci. 24, 168–78.PubMedCrossRefGoogle Scholar
  35. 35.
    Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., and Malinow, R. (2003) APP processing and synaptic function. Neuron 37, 925–37.PubMedCrossRefGoogle Scholar
  36. 36.
    Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., and Slutsky, I. (2009) Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat. Neurosci. 12, 1567–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Podlisny, M. B., Walsh, D. M., Amarante, P., Ostaszewski, B. L., Stimson, E. R., Maggio, J. E., Teplow, D. B., and Selkoe, D. J. (1998) Oligomerization of endogenous and synthetic amyloid beta-protein at nanomolar levels in cell culture and stabilization of monomer by congo red. Biochemistry 37, 3602–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., Regan, C. M., Walsh, D. M., Sabatini, B. L., and Selkoe, D. J. (2008) Amyloid-b protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14, 837–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Lesné, S., MT, K., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., and Ashe, K. H. (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–57.PubMedCrossRefGoogle Scholar
  40. 40.
    Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., and Klein, W. L. (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 95, 6448–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Klein, W. L., Krafft, G. A., and Finch, C. E. (2001) Targeting small Ab oligomers: the solution to an Alzheimer’s disease conundrum. Trends Neurosci. 24, 219–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., and LaDu, M. J. (2002) Oligomeric and fibrillar species of amyloid-b peptides differentially affect neuronal viability. J. Biol. Chem. 277, 32046–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Wood, J. G., Mirra, S. S., Pollock, N. J., and Binder, L. I. (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (t). Proc. Natl. Acad. Sci. U.S.A. 83, 4040–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Kosik, K. S., Joachim, C. L., and Selkoe, D. J. (1986) Microtubule-associated protein tau (t) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 83, 4044–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Grundke-Iqbal, I., Iqbal, K., Quinlan, M., Tung, Y. C., Zaidi, M. S., and Wisniewski, H. M. (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–9.PubMedGoogle Scholar
  46. 46.
    Lee, V. M., Balin, B. J., Otvos, L., Jr., and Trojanowski, J. Q. (1991) A68: a major subunit of paired helical filaments and deri­vatized forms of normal Tau. Science 251, 675–8.PubMedCrossRefGoogle Scholar
  47. 47.
    SantaCruz, K., Lewis, J., Spires, T., Paulson, J., Kotilinek, L., Ingelsson, M., Guimaraes, A., DeTure, M., Ramsden, M., McGowan, E., Forster, C., Yue, M., Orne, J., Janus, C., Mariash, A., Kuskowski, M., Hyman, B., Hutton, M., and Ashe, K. H. (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., and Mucke, L. (2007) Reducing endogenous tau ameliorates amyloid b-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Dickey, C. A., Dunmore, J., Lu, B., Wang, J. W., Lee, W. C., Kamal, A., Burrows, F., Eckman, C., Hutton, M., and Petrucelli, L. (2006) HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 20, 753–55.PubMedGoogle Scholar
  50. 50.
    Chun, W., Waldo, G. S., and Johnson, G. V. (2007) Split GFP complementation assay: a novel approach to quantitatively measure aggregation of tau in situ: effects of GSK3β activation and caspase 3 cleavage. J. Neurochem. 103, 2529–39.PubMedCrossRefGoogle Scholar
  51. 51.
    Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., Myers, R. H., Pericak-Vance, M. A., Risch, N., and van Duijn, C. M. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. J. Am. Med. Assoc. 278, 1349–56.CrossRefGoogle Scholar
  52. 52.
    Agosta, F., Vossel, K. A., Miller, B. L., Migliaccio, R., Bonasera, S. J., Filippi, M., Boxer, A. L., Karydas, A., Possin, K. L., and Gorno-Tempini, M. L. (2009) Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc. Natl. Acad. Sci. U.S.A. 106, 2018–22.PubMedCrossRefGoogle Scholar
  53. 53.
    Götz, J., and Ittner, L. M. (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat. Rev. Neurosci. 9, 532–44.PubMedCrossRefGoogle Scholar
  54. 54.
    Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O’Campo, K., Hardy, J., Prada, C. M., Eckman, C., Younkin, S., Hsiao, K., and Duff, K. (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat. Med. 4, 97–100.PubMedCrossRefGoogle Scholar
  55. 55.
    Westerman, M. A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L. H., Carlson, G. A., Younkin, S. G., and Ashe, K. H. (2002) The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci. 22, 1858–67.PubMedGoogle Scholar
  56. 56.
    Kobayashi, D. T., and Chen, K. S. (2005) Beha­vioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes Brain Behav. 4, 173–96.PubMedCrossRefGoogle Scholar
  57. 57.
    Palop, J. J., Jones, B., Kekonius, L., Chin, J., Yu, G.-Q., Raber, J., Masliah, E., and Mucke, L. (2003) Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proc. Natl. Acad. Sci. U.S.A. 100, 9572–77.PubMedCrossRefGoogle Scholar
  58. 58.
    Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., and Hyman, B. T. (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–39.PubMedCrossRefGoogle Scholar
  59. 59.
    Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley-Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., and Irizarry, M. C. (2004) Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62, 925–31.PubMedCrossRefGoogle Scholar
  60. 60.
    Giannakopoulos, P., Gold, G., Kövari, E., von Gunten, A., Imhof, A., Bouras, C., and Hof, P. R. (2007) Assessing the cognitive impact of Alzheimer disease pathology and vascular burden in the aging brain: the Geneva experience. Acta Neuropathol. 113, 1–12.PubMedCrossRefGoogle Scholar
  61. 61.
    De Vos, K. J., Grierson, A. J., Ackerley, S., and Miller, C. C. (2008) Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151–73.PubMedCrossRefGoogle Scholar
  62. 62.
    Palop, J. J., Chin, J., Roberson, E. D., Wang, J., Thwin, M. T., Bien-Ly, N., Yoo, J., Ho, K. O., Yu, G.-Q., Kreitzer, A., Finkbeiner, S., Noebels, J. L., and Mucke, L. (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55, 697–711.PubMedCrossRefGoogle Scholar
  63. 63.
    Palop, J. J., and Mucke, L. (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch. Neurol. 66, 435–40.PubMedCrossRefGoogle Scholar
  64. 64.
    Levenson, J. M., and Sweatt, J. D. (2005) Epigenetic mechanisms in memory formation. Nat. Rev. Neurosci. 6, 108–18.PubMedCrossRefGoogle Scholar
  65. 65.
    Ricobaraza, A., Cuadrado-Tejedor, M., Pérez-Mediavilla, A., Frechilla, D., Del Río, J., and García-Osta, A. (2009) Phenyl­butyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 34, 1721–32.PubMedCrossRefGoogle Scholar
  66. 66.
    Kilgore, M., Miller, C. A., Fass, D. M., Hennig, K. M., Haggarty, S. J., Sweatt, J. D., and Rumbaugh, G. (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35, 870–80.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  • Erik D. Roberson
    • 1
  1. 1.Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental TherapeuticsUniversity of Alabama at BirminghamBirminghamUSA

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