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Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease.
- Source :
-
Neurobiology of aging [Neurobiol Aging] 2013 Sep; Vol. 34 (9), pp. 2081-90. Date of Electronic Publication: 2013 Apr 09. - Publication Year :
- 2013
-
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.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Alzheimer Disease therapy
Amyloid beta-Peptides metabolism
Animals
Cells, Cultured
DNA genetics
Epigenesis, Genetic genetics
Female
Humans
Male
Mice
Mice, Transgenic
Molecular Targeted Therapy
Neuroblastoma metabolism
Neurons metabolism
Pregnancy
Rats
Rats, Sprague-Dawley
Solubility
Transcriptional Activation
Alzheimer Disease genetics
Amyloid beta-Peptides physiology
Histones metabolism
Homeostasis genetics
Neocortex metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-1497
- Volume :
- 34
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Neurobiology of aging
- Publication Type :
- Academic Journal
- Accession number :
- 23582659
- Full Text :
- https://doi.org/10.1016/j.neurobiolaging.2012.12.028