Beta-amyloid-induced neurotoxicity of a hybrid septal cell line associated with increased tau phosphorylation and expression of beta-amyloid precursor protein.
Recent evidence suggests that beta-amyloid peptide (beta-AP) may induce tau protein phosphorylation, resulting in loss of microtubule binding capacity and formation of paired helical filaments. The mechanism by which beta-AP increases tau phosphorylation, however, is unclear. Using a hybrid septal cell line, SN56, we demonstrate that aggregated beta-AP(1-40) treatment caused cell injury. Accompanying the cell injury, the levels of phosphorylated tau as well as total tau were enhanced as detected immunochemically by AT8, PHF-1, Tau-1, and Tau-5 antibodies. Alkaline phosphatase treatment abolished AT8 and PHF-1 immunoreactivity, confirming that the tau phosphorylation sites were at least at Ser(199/202) and Ser396. In association with the increase in tau phosphorylation, the immunoreactivity of cell-associated and secreted beta-amyloid precursor protein (beta-APP) was markedly elevated. Application of antisense oligonucleotide to beta-APP reduced expression of beta-APP and immunoreactivity of phosphorylated tau. Control peptide beta-AP(1-28) did not produce significant effects on tau phosphorylation, although it slightly increased cell-associated beta-APP. These results suggest that betaAP(1-40)-induced tau phosphorylation may be associated with increased beta-APP expression in degenerated neurons.
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W D
WD
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, U.S.A.
Xie
W J
WJ
Kong
R
R
Appel
S H
SH
D000469:Alkaline Phosphatase / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D006822:Hybrid Cells; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects; D009447:Neuroblastoma; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D000469:Alkaline Phosphatase