The amyloid peptide induces early genotoxic damage in human preneuron NT2.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the extracellular deposition of amyloid beta-peptide (Abeta) in the brain. Abeta is involved in the pathogenesis of AD but the molecular mechanisms of its neurotoxicity are unknown. Here, we report that Abeta exposure on human preneuronal NT2 cells provoked a strong and early up-regulation of growth arrest and DNA damage inducible gene (Gadd45 mRNA), an indicator of DNA damage and DNA excision-repair processes, strongly suggesting that Abeta causes an early DNA strand breakage leading to a cellular DNA repair response. Comet assay clearly demonstrated that both full-length Abeta (1-42), and its minimal cytotoxic fragment Abeta (25-35), caused DNA breakage as early as 3h after the start of Abeta exposure. This extensive DNA damage provoked by Abeta constitutes an early event in the pathogenic cascade leading to neuronal death which could contribute to the neuropathogenesis of AD.
Santiard-Baron
D
D
Inserm U383 and CNRS UMR 8602, Hôpital Necker, 149 rue de Sèvres, 75015, Paris, France.
Lacoste
A
A
Ellouk-Achard
S
S
Soulié
C
C
Nicole
A
A
Sarasin
A
A
Ceballos-Picot
I
I
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D015152:Blotting, Northern; D002478:Cells, Cultured; D020552:Comet Assay; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D051020:bcl-X Protein; D000097642:GADD45 Proteins
D016229:Amyloid beta-Peptides; D004247:DNA; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000097642:GADD45 Proteins; C494811:BCL2L1 protein, human; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35)