title: Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease.
abstract: Amyloid-β peptide (Aβ) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aβ at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results in vitro and in vivo indicate that multimeric soluble Aβ may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aβ could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.
authors.affiliation: Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christina Unger
authors.initials: CU
authors.lastname: Lithner
authors.forename: Pascale N
authors.initials: PN
authors.lastname: Lacor
authors.forename: Wei-Qin
authors.initials: WQ
authors.lastname: Zhao
authors.forename: Tamanna
authors.initials: T
authors.lastname: Mustafiz
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Caterina M
authors.initials: CM
authors.lastname: Hernandez
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D019579:Neocortex / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D015533:Transcriptional Activation
chemical_list: D016229:Amyloid beta-Peptides; D006657:Histones; D004247:DNA