Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease

Christina Unger Lithner, Pascale N. Lacor, Wei Qin Zhao, Tamanna Mustafiz, William L. Klein, J. David Sweatt, Caterina M. Hernandez

Research output: Contribution to journalArticle

27 Scopus citations

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 invitro and invivo 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.

Original languageEnglish (US)
Pages (from-to)2081-2090
Number of pages10
JournalNeurobiology of Aging
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2013

Keywords

  • Alzheimer's disease
  • Amyloid-β peptide/protein
  • Dendritic spine
  • Drebrin
  • Epigenetics
  • Histone H3
  • Histone acetylation
  • Histone methylation
  • Neocortex
  • Soluble Aβ/Aβ-derived diffusible ligand (ADDL)
  • Tg2576 transgenic mouse model

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Lithner, C. U., Lacor, P. N., Zhao, W. Q., Mustafiz, T., Klein, W. L., Sweatt, J. D., & Hernandez, C. M. (2013). Disruption of neocortical histone H3 homeostasis by soluble Aβ: Implications for Alzheimer's disease. Neurobiology of Aging, 34(9), 2081-2090. https://doi.org/10.1016/j.neurobiolaging.2012.12.028