Skip to main content
SpringerLink
Log in

Epigenetics of Alzheimer’s Disease and Frontotemporal Dementia

  • Review
  • Published:
Neurotherapeutics

Abstract

This article will review the recent advances in the understanding of the role of epigenetic modifications and the promise of future epigenetic therapy in neurodegenerative dementias, including Alzheimer’s disease and frontotemporal dementia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263–269.

    PubMed  Google Scholar 

  2. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615–1621.

    PubMed  CAS  Google Scholar 

  3. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States. Alzheimers Dement 2011;7:80–93.

    PubMed  Google Scholar 

  4. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 2010;9:702–716.

    PubMed  CAS  Google Scholar 

  5. Boxer AL, Gold M, Huey E, et al. Frontotemporal degeneration, the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development. Alzheimers Dement 2012;9:188–176.

    Google Scholar 

  6. Klucken J, McLean PJ, Gomez-Tortosa E, Ingelsson M, Hyman BT. Neuritic alterations and neural system dysfunction in Alzheimer’s disease and dementia with Lewy bodies. Neurochem Res 2003;28:1683–1691.

    PubMed  CAS  Google Scholar 

  7. Vassar R. BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci 2004;23:105–114.

    PubMed  CAS  Google Scholar 

  8. Xia W. Role of presenilin in gamma-secretase cleavage of amyloid precursor protein. Exp Gerontol 2000;35:453–460.

    PubMed  CAS  Google Scholar 

  9. Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 2006;96:732–742.

    PubMed  CAS  Google Scholar 

  10. Findeis MA. The role of amyloid beta peptide 42 in Alzheimer’s disease. Pharmacol Ther 2007;116:266–286.

    PubMed  CAS  Google Scholar 

  11. Niemitz E. TREM2 and Alzheimer’s disease. Nat Genet 2012;45:11–11.

    Google Scholar 

  12. Van Der Flier WM, Pijnenburg YA, Fox NC, Scheltens P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE epsilon 4 allele. Lancet 2011;10:280–288

    Google Scholar 

  13. Campion D, Dumanchin C, Hannequin D, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 1999;65:664–670.

    PubMed  CAS  Google Scholar 

  14. Lambert J-C, Amouyel P. Genetic heterogeneity of Alzheimer’s disease: complexity and advances. Psychoneuroendocrinology 2007;32(Suppl. 1):S62-70.

    PubMed  CAS  Google Scholar 

  15. Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type: Evidence of subgroups. Neurology 1985;35:453–453.

    PubMed  CAS  Google Scholar 

  16. Gold G, Blouin J-L, Herrmann FR, et al. Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers. Am J Med Genet B Neuropsychiatr Genet 2003;119B:44–47.

    PubMed  Google Scholar 

  17. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76:1006–1014.

    PubMed  Google Scholar 

  18. Seelaar H, Rohrer JD, Pijnenburg YAL, Fox NC, Van Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 2011;82:476–486.

    PubMed  Google Scholar 

  19. Majounie E, Renton AE, Mok K, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012;11:323–330.

    PubMed  CAS  Google Scholar 

  20. Urwin H, Ghazi-Noori S, Collinge J, Isaacs A. The role of CHMP2B in frontotemporal dementia. Biochem Soc Trans 2009;37:208–212.

    PubMed  CAS  Google Scholar 

  21. Isaacs AM, Johannsen P, Holm I, Nielsen JE. Frontotemporal dementia caused by CHMP2B mutations. Curr Alzheimer Res 2011;8:246–251.

    PubMed  CAS  Google Scholar 

  22. Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer’s disease. Lancet Neurol 2013;12:92–104.

    PubMed  CAS  Google Scholar 

  23. Rademakers R, Mackenzie IRA. Recent advances in the molecular basis of frontotemporal dementia. Nat Rev Neurol 2013;8:423–434.

    Google Scholar 

  24. Ambegaokar SS, Jackson GR. Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation. Hum Mol Genet 2011;20:4947–4977.

    PubMed  CAS  Google Scholar 

  25. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 2009;27:351–357.

    PubMed  CAS  Google Scholar 

  26. Griffith JS, Mahler HR. DNA Ticketing theory of memory. Nature 1969;223:580–582.

    PubMed  CAS  Google Scholar 

  27. Kouzarides T. Chromatin modifications and their function. Cell 2007;128:693–705.

    PubMed  CAS  Google Scholar 

  28. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000;403:41–45.

    PubMed  CAS  Google Scholar 

  29. Rando OJ. Combinatorial complexity in chromatin structure and function: revisiting the histone code. Curr Opin Genet Develop 2012;22:148–155.

    CAS  Google Scholar 

  30. Tweedie-Cullen RY, Brunner AM, Grossmann J, et al. Identification of combinatorial patterns of post-translational modifications on individual histones in the mouse brain. PloS One 2012;7:e36980.

    PubMed  CAS  Google Scholar 

  31. Costa FF. Non-coding RNAs, epigenetics and complexity. Gene 2008;410:9–17.

    PubMed  CAS  Google Scholar 

  32. Champagne FA. Epigenetics and developmental plasticity across species. Develop Psychobiol 2013;55:33–41.

    Google Scholar 

  33. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163–167.

    PubMed  CAS  Google Scholar 

  34. Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 2006;174:341–348.

    PubMed  Google Scholar 

  35. Liu L, Van Groen T, Kadish I, Tollefsbol TO. DNA methylation impacts on learning and memory in aging. Neurobiol Aging 2009;30:549–560.

    PubMed  CAS  Google Scholar 

  36. Peleg S, Sananbenesi F, Zovoilis A, et al. (2010). Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756.

    PubMed  CAS  Google Scholar 

  37. Rando TA. Epigenetics and aging. Exp Gerontol 2010;45:253–254.

    PubMed  Google Scholar 

  38. Alarcón JM, Malleret G, Touzani K, et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 2004;42:947–959.

    PubMed  Google Scholar 

  39. Jiang Y, Langley B, Lubin FD, et al. Epigenetics in the nervous system. J Neurosci 2008;28:11753–11759.

    PubMed  CAS  Google Scholar 

  40. Levenson JM, Sweatt JD. Epigenetic mechanisms in memory formation. Nat Rev Neurosci 2005;6:108–118.

    PubMed  CAS  Google Scholar 

  41. Hsieh J, Gage FH. Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 2005;17:664–671.

    PubMed  CAS  Google Scholar 

  42. Hirabayashi Y, Gotoh Y. Epigenetic control of neural precursor cell fate during development. Nat Rev Neurosci 2010;11:377–388.

    PubMed  CAS  Google Scholar 

  43. Numata S, Ye T, Hyde TM, et al. DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet 2012;90:260–272.

    PubMed  CAS  Google Scholar 

  44. Siegmund KD, Connor CM, Campan M, et al. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PloS One 2007;2:e895.

    PubMed  Google Scholar 

  45. Szulwach KE, Li X, Li Y, et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 2011;14:1607–1616.

    PubMed  CAS  Google Scholar 

  46. Peter CJ, Akbarian S. Balancing histone methylation activities in psychiatric disorders. Trends Mol Med 2011;17:372–379.

    PubMed  CAS  Google Scholar 

  47. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007;8:355–367.

    PubMed  CAS  Google Scholar 

  48. Clayton-Smith J, Watson P, Ramsden S, Black G. Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males. Lancet 2000;356:830–832.

    PubMed  CAS  Google Scholar 

  49. Meloni I, Bruttini M, Longo I, et al. A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am J Hum Genet 2000;67:982–985.

    PubMed  CAS  Google Scholar 

  50. Klein CJ, Botuyan M-V, Wu Y, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 2011;43: 595–600.

    PubMed  CAS  Google Scholar 

  51. De Greef JC, Wang J, Balog J, et al. Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am J Hum Genet 2011;88:796–804.

    PubMed  Google Scholar 

  52. Xu GL, Bestor TH, Bourc’his D, et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999;402:187–191.

    PubMed  CAS  Google Scholar 

  53. Covington HE, Maze I, Sun H, et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 2011;71:656–670.

    PubMed  CAS  Google Scholar 

  54. Lim DA, Huang Y-C, Swigut T, et al. Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells. Nature 2009;458:529–533.

    PubMed  CAS  Google Scholar 

  55. Pereira JD, Sansom SN, Smith J, Dobenecker M-W, Tarakhovsky A, Livesey FJ. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci U S A 2010;107:15957–15962.

    PubMed  CAS  Google Scholar 

  56. Adegbola A, Gao H, Sommer S, Browning M. A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). Am J Med Genet A 2008;146A:505–511.

    PubMed  CAS  Google Scholar 

  57. Burgold T, Spreafico F, De Santa F, et al. The histone H3 lysine 27-specific demethylase Jmjd3 is required for neural commitment. PloS One 2008;3:e3034.

    PubMed  Google Scholar 

  58. Tahiliani M, Mei P, Fang R, et al. The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 2007;447:601–605.

    PubMed  CAS  Google Scholar 

  59. Gräff J, Tsai L-H. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 2013;14:97–111.

    PubMed  Google Scholar 

  60. Qureshi IA, Mehler MF. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci 2012;13:528–541.

    PubMed  CAS  Google Scholar 

  61. Niland CN, Merry CR, Khalil AM. Emerging roles forlong non-coding RNAs in cancer and neurological disorders. Front Genet 2012;3:25.

    PubMed  CAS  Google Scholar 

  62. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 2008;105:716–721.

    PubMed  CAS  Google Scholar 

  63. Spadaro PA, Bredy TW. Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders. Front Genet 2012;3:132.

    PubMed  CAS  Google Scholar 

  64. Ng S-Y, Lin L, Soh BS, Stanton LW. Long noncoding RNAs in development and disease of the central nervous system. Trends Genet 2013;29:461–468.

    PubMed  CAS  Google Scholar 

  65. Telese F, Gamliel A, Skowronska-Krawczyk D, Garcia-Bassets I, Rosenfeld MG. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron 2013;77:606–623.

    PubMed  CAS  Google Scholar 

  66. Tushir JS, Akbarian S. Chromatin-bound RNA and the neurobiology of psychiatric disease. Neuroscience 2013 Jul 3 [Epub ahead of print].

  67. Chan TA. Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management. Onco Targets Ther 2013;6:223–232.

    PubMed  Google Scholar 

  68. Mack GS. To selectivity and beyond. Nat Biotechnol 2010;28:1259–1266.

    PubMed  CAS  Google Scholar 

  69. Barrachina M, Ferrer I. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol 2009;68:880–891.

    PubMed  CAS  Google Scholar 

  70. Brohede J, Rinde M, Winblad B, Graff C. A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease. J Neurogenet 2010;24:179–181.

    PubMed  CAS  Google Scholar 

  71. Bakulski KM, Dolinoy DC, Sartor MA, et al. Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 2012;29:571–588.

    PubMed  CAS  Google Scholar 

  72. Bollati V, Galimberti D, Pergoli L, et al. DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun 2011;25:1078–1083.

    PubMed  CAS  Google Scholar 

  73. Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Abeta by neprilysin. Science 2001;292:1550–1552.

    PubMed  CAS  Google Scholar 

  74. Chen K-L, Wang SS-S, Yang Y-Y, Yuan R-Y, Chen R-M, Hu C-J. The epigenetic effects of amyloid-beta(1–40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun 2009;378:57–61.

    PubMed  CAS  Google Scholar 

  75. Galimberti D, D’Addario C, Dell’osso B, et al. Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration. Neurol Sci 2013;34:899–903.

    PubMed  Google Scholar 

  76. Xi Z, Zinman L, Moreno D, Schymick J, et al. Hypermethylation of the CpG Island Near the G4C2 Repeat in ALS with a C9orf72 Expansion. Am J Hum Genet 2013 May 22 [Epub ahead of print].

  77. Chan A, Shea TB. Folate deprivation increases presenilin expression, gamma-secretase activity, and Abeta levels in murine brain: potentiation by ApoE deficiency and alleviation by dietary S-adenosyl methionine. J Neurochem 2007;102:753–760.

    PubMed  CAS  Google Scholar 

  78. Fuso A, Seminara L, Cavallaro RA, D’Anselmi F, Scarpa S. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 2005;28:195–204.

    PubMed  CAS  Google Scholar 

  79. Fuso A, Nicolia V, Cavallaro RA, et al. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci 2008;37:731–746.

    PubMed  CAS  Google Scholar 

  80. Lin H-C, Hsieh H-M, Chen Y-H, Hu M-L. S-Adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters. Neurotoxicology 2009;30:622–627.

    PubMed  CAS  Google Scholar 

  81. Scarpa S, Fuso A, D’Anselmi F, Cavallaro RA. Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS Lett 2003;541:145–148.

    PubMed  CAS  Google Scholar 

  82. Bihaqi SW, Zawia NH. Alzheimer’s disease biomarkers and epigenetic intermediates following exposure to Pb in vitro. Curr Alzheimer Res 2012;9:555–562.

    PubMed  CAS  Google Scholar 

  83. Li Y-Y, Chen T, Wan Y, Xu S. Lead exposure in pheochromocytoma cells induces persistent changes in amyloid precursor protein gene methylation patterns. Environ Toxicol 2012;27:495–502.

    PubMed  CAS  Google Scholar 

  84. Guo X, Wu X, Ren L, Liu G, Li L. Epigenetic mechanisms of amyloid-β production in anisomycin-treated SH-SY5Y cells. Neuroscience 2011;194:272–281.

    PubMed  CAS  Google Scholar 

  85. Rao JS, Keleshian VL, Klein S, Rapoport SI. Epigenetic modifications in frontal cortex from Alzheimer ’ s disease and bipolar disorder patients. Transl Psychiatry 2012;2:1–7.

    CAS  Google Scholar 

  86. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009;324:930–935.

    PubMed  CAS  Google Scholar 

  87. Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PloS One 2009;4:e6617.

    PubMed  Google Scholar 

  88. Sandi C, Al-Mahdawi S, Pook MA. Epigenetics in Friedreich’s ataxia: challenges and opportunities for therapy. Genet Res Int 2013;852080.

  89. Chiurazzi P, Pomponi MG, Willemsen R, Oostra BA, Neri G. In vitro reactivation of the FMR1 gene involved in fragile X syndrome. Hum Mol Genet 1998;7:109–113.

    PubMed  CAS  Google Scholar 

  90. Chiurazzi P, Grazia Pomponi M, Pietrobono R, Bakker CE, Neri G, Oostra BA. Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum Mol Genet 1999;8:2317–2323.

    PubMed  CAS  Google Scholar 

  91. Rice JC, Briggs SD, Ueberheide B, et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 2003;12:1591–1598.

    PubMed  CAS  Google Scholar 

  92. Gräff J, Tsai L-H. The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 2013;53:311–330.

    PubMed  Google Scholar 

  93. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;10:32–42.

    PubMed  CAS  Google Scholar 

  94. Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Develop 1998;12:599–606.

    PubMed  CAS  Google Scholar 

  95. Kubicek S, Gilbert JC, Fomina-Yadlin D, et al. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. Proce Natl Acad Sci U S A 2012;109:5364–5369.

    CAS  Google Scholar 

  96. Koolen DA, Kramer JM, Neveling K, et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet 2012;44:639–641.

    PubMed  CAS  Google Scholar 

  97. Kerimoglu C, Agis-Balboa RC, Kranz A, et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci  2013;33:3452–3464.

    PubMed  CAS  Google Scholar 

  98. Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 2004;42:961–972.

    PubMed  CAS  Google Scholar 

  99. Broide RS, Redwine JM, Aftahi N, Young W, Bloom FE, Winrow CJ. Distribution of histone deacetylases 1–11 in the rat brain. J Mol Neurosci 2007;31:47–58.

    PubMed  CAS  Google Scholar 

  100. McQuown SC, Barrett RM, Matheos DP, et al. HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 2011;31:764–774.

    PubMed  CAS  Google Scholar 

  101. Nelson ED, Bal M, Kavalali ET, Monteggia LM. Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission. J Neurophysiol 2011;106:193–201.

    PubMed  CAS  Google Scholar 

  102. Guan J-S, Haggarty SJ, Giacometti E, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009;459:55–60.

    PubMed  CAS  Google Scholar 

  103. Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 2004;279:40545–40559.

    PubMed  CAS  Google Scholar 

  104. Gräff J, Rei D, Guan J-S, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012;483:222–226.

    PubMed  Google Scholar 

  105. Haggarty SJ, Tsai L-H. Probing the role of HDACs and mechanisms of chromatin-mediated neuroplasticity. Neurobiol Learn Mem 2011;96:41–52.

    PubMed  CAS  Google Scholar 

  106. Ding H, Dolan PJ, Johnson GVW. Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem 2008;106:2119–2130.

    PubMed  CAS  Google Scholar 

  107. Govindarajan N, Rao P, Burkhardt S, et al. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med 2013;5:52–63.

    PubMed  CAS  Google Scholar 

  108. Kim M-S, Akhtar MW, Adachi M, et al. An essential role for histone deacetylase 4 in synaptic plasticity and memory formation. J Neurosci 2012;32: 10879–10886.

    PubMed  CAS  Google Scholar 

  109. Harrison IF, Dexter DT. Epigenetic targeting of histone deacetylase: Therapeutic potential in Parkinson’s disease? Pharmacol Ther 2013 May 24 [Epub ahead of print].

  110. Bradner JE, West N, Grachan ML, et al. Chemical phylogenetics of histone deacetylases. Nat Chem Biol 2010;6:238–243.

    PubMed  CAS  Google Scholar 

  111. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai L-H. Recovery of learning and memory is associated with chromatin remodelling. Nature 2007;447:178–182.

    PubMed  CAS  Google Scholar 

  112. Morris MJ, Mahgoub M, Na ES, Pranav H, Monteggia LM. Loss of histone deacetylase 2 improves working memory and accelerates extinction learning. J Neurosci 2013;33:6401–6411.

    PubMed  CAS  Google Scholar 

  113. Kim D, Frank CL, Dobbin MM, et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 2008;60:803–817.

    PubMed  CAS  Google Scholar 

  114. Cenik B, Sephton CF, Dewey CM, et al. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 2011;286:16101–16108.

    PubMed  CAS  Google Scholar 

  115. Min S-W, Cho S-H, Zhou Y, et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010;67:953–966.

    PubMed  CAS  Google Scholar 

  116. Krichevsky AM, Sonntag K-C, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 2006;24:857–864.

    PubMed  CAS  Google Scholar 

  117. De Pietri Tonelli D, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB. miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development 2008;135:3911–3921

    PubMed  Google Scholar 

  118. Coppedè F. Advances in the Genetics and Epigenetics of Neurodegenerative Diseases. Epigenet Neurodegener Dis 2013;1:2–30.

    Google Scholar 

  119. Hébert SS, Papadopoulou AS, Smith P, et al. Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet 2010;19:3959–3969.

    PubMed  Google Scholar 

  120. Cogswell JP, Ward J, Taylor IA, et al. Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 2008;14:27–41.

    PubMed  CAS  Google Scholar 

  121. Julien C, Tremblay C, Emond V, et al. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 2009;68:48–58.

    PubMed  CAS  Google Scholar 

  122. Renoux AJ, Todd PK. Neurodegeneration the RNA way. Prog Neurobiol 2012;97:173–189.

    PubMed  CAS  Google Scholar 

  123. Tan L, Yu J-T, Hu N, Tan L. Non-coding RNAs in Alzheimer’s disease. Mol Neurobiol 2013;47:382–393.

    PubMed  CAS  Google Scholar 

  124. Hébert SS, Horré K, Nicolaï L, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 2008;105:6415–6420.

    PubMed  Google Scholar 

  125. Yao J, Hennessey T, Flynt A, Lai E, Beal MF, Lin MT. MicroRNA-related cofilin abnormality in Alzheimer’s disease. PloS One 2010;5:e15546.

    PubMed  CAS  Google Scholar 

  126. Boissonneault V, Plante I, Rivest S, Provost P. MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. J Biol Chem 2009;284:1971–1981.

    PubMed  CAS  Google Scholar 

  127. Wang W-X, Rajeev BW, Stromberg AJ, et al. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 2008;28:1213–1223.

    PubMed  Google Scholar 

  128. Hébert SS, Horré K, Nicolaï L, et al. MicroRNA regulation of Alzheimer’s Amyloid precursor protein expression. Neurobiol Dis 2009;33:422–428.

    PubMed  Google Scholar 

  129. Long JM, Lahiri DK. MicroRNA-101 downregulates Alzheimer’s amyloid-β precursor protein levels in human cell cultures and is differentially expressed. Biochem Biophys Res Commun 2011;404:889–895.

    PubMed  CAS  Google Scholar 

  130. Faghihi MA, Modarresi F, Khalil AM, et al. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 2008;14:723–730.

    PubMed  CAS  Google Scholar 

  131. Saxena A, Carninci P. Long non-coding RNA modifies chromatin: epigenetic silencing by long non-coding RNAs. Bioessays  2011;33:830–839.

    PubMed  CAS  Google Scholar 

  132. Fang M, Wang J, Zhang X, et al. The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer’s disease. Toxicol Lett 2012;209:94–105.

    PubMed  CAS  Google Scholar 

  133. Perry MM, Williams AE, Tsitsiou E, Larner-Svensson HM, Lindsay MA. Divergent intracellular pathways regulate interleukin-1beta-induced miR-146a and miR-146b expression and chemokine release in human alveolar epithelial cells. FEBS Lett 2009;583:3349–3355.

    PubMed  CAS  Google Scholar 

  134. Taganov KD, Boldin MP, Chang K-J, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 2006;103:12481–12486.

    PubMed  CAS  Google Scholar 

  135. Tollervey JR, Curk T, Rogelj B, et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 2011;14:452–458.

    PubMed  CAS  Google Scholar 

  136. Kawahara Y, Mieda-Sato A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci U S A 2012;109:3347–3352.

    PubMed  CAS  Google Scholar 

  137. Lai CP-K, Breakefield XO. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol 2012;3:228.

    PubMed  CAS  Google Scholar 

  138. Modarresi F, Faghihi MA, Lopez-Toledano MA, et al. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 2012;30:453–459.

    PubMed  CAS  Google Scholar 

  139. Pardridge WM. The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2005;2:3–14.

    PubMed  Google Scholar 

  140. Hockly E, Richon VM, Woodman B, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A 2003;100:2041–2046.

    PubMed  CAS  Google Scholar 

  141. Kwa FAA, Balcerczyk A, Licciardi P, El-Osta A, Karagiannis TC. Chromatin modifying agents - the cutting edge of anticancer therapy. Drug Discov Today 2011;16:543–547.

    PubMed  CAS  Google Scholar 

  142. Rai M, Soragni E, Jenssen K, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PloS One 2008;3:e1958.

    PubMed  Google Scholar 

  143. Cuadrado-Tejedor M, Oyarzabal J, Lucas MP, Franco R, García-Osta A. Epigenetic drugs in Alzheimer’s disease. BioMolecular Concepts 2013 Jul 27 [Epub ahead of print].

  144. Martinet N, Michel BY, Bertrand P, Benhida R. Small molecules DNA methyltransferases inhibitors. Med Chem Comm 2011;3:263.

    Google Scholar 

  145. Subramanian S, Bates SE, Wright JJ, Espinoza-Delgado I, Piekarz RL. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals 2010;3:2751–2767.

    CAS  Google Scholar 

  146. Petruccelli LA, Dupéré-Richer D, Pettersson F, Retrouvey H, Skoulikas S, Miller WH. Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. PloS One 2011;6:e20987.

    PubMed  CAS  Google Scholar 

  147. Alzoubi KH, Khabour OF, Jaber AG, Al-Azzam SI, Mhaidat NM, Masadeh MM. Tempol prevents genotoxicity induced by vorinostat: role of oxidative DNA damage. Cytotechnology 2013 Jun 13 [Epub ahead of print].

  148. Kreuter J. Nanoparticulate systems for brain delivery of drugs. Adv Drug Deliv Rev 2001;47:65–81.

    PubMed  CAS  Google Scholar 

  149. Kumar P, Wu H, McBride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature 2007;448:39–43.

    PubMed  CAS  Google Scholar 

  150. Pardridge WM. Intravenous, non-viral RNAi gene therapy of brain cancer. Exp Opin Biol Ther 2004;4:1103–1113.

    CAS  Google Scholar 

  151. Masserini M. Nanoparticles for brain drug delivery. ISRN Biochemistry 2013; 1–18.

  152. Pastori C, Wahlestedt C. Involvement of long noncoding RNAs in diseases affecting the central nervous system. RNA Biology 2012;9:860–870.

    PubMed  CAS  Google Scholar 

  153. Miller CP, Singh MM, Rivera-Del Valle N, Manton CA, Chandra J. Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors. J Biomed Biotechnol 2011;514261.

  154. Bohacek J, Mansuy IM. Epigenetic inheritance of disease and disease risk. Neuropsychopharmacology 2013;38:220–236.

    PubMed  CAS  Google Scholar 

  155. Hackett JA, Sengupta R, Zylicz JJ, et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 2013;339:448–452.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

C.S.V. is supported by the Tau Consortium and the NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691). S.S. is supported by the Goldsmith Foundation, New York, NY. G.C. is supported by the John Douglas French Alzheimer’s Disease Foundation and the Tau Consortium.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Authors and Affiliations

  1. Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    Chendhore S. Veerappan & Giovanni Coppola

  2. Burke Research Center, Weill Medical College of Cornell University, White Plains, NY, USA

    Sama Sleiman

  3. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Giovanni Coppola

Authors
  1. Chendhore S. Veerappan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sama Sleiman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giovanni Coppola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chendhore S. Veerappan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 1.19 MB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veerappan, C.S., Sleiman, S. & Coppola, G. Epigenetics of Alzheimer’s Disease and Frontotemporal Dementia. Neurotherapeutics 10, 709–721 (2013). https://doi.org/10.1007/s13311-013-0219-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-013-0219-0

Keywords

Search

Navigation