Disruption of neocortical histone H3 homeostasis by soluble A beta: implications for Alzheimer%26apos;s disease

作者：Lithner Christina Unger; Lacor Pascale N; Zhao Wei Qin; Mustafiz Tamanna; Klein William L; Sweatt J David; Hernandez Caterina M^*

来源：Neurobiology of Aging, 2013, 34(9): 2081-2090.

DOI：10.1016/j.neurobiolaging.2012.12.028

• Alzheimer%26apos
• s disease
• Epigenetics
• Histone H3
• Histone acetylation
• Histone methylation
• Amyloid-beta peptide/protein
• Soluble A beta/A beta-derived diffusible ligand (ADDL)
• neocortex
• Drebrin
• Tg2576 transgenic mouse model
• Dendritic spine

Amyloid-beta peptide (A beta) fragment misfolding may play a crucial role in the progression of Alzheimer%26apos;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 A beta 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 A beta 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 A beta could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

• 出版日期2013-9
• 单位西北大学