Beta/A4-evoked degeneration of differentiated SH-SY5Y human neuroblastoma cells.
beta/A4 peptides are known to induce neurodegeneration in cultures of rat brain cells and rat neural cell lines (Yankner et al: Science 250:279-282, 1990; Behl et al: Biochem Biophys Res Commun 186:944-950, 1992). The current data show that these peptides induce similar neurodegeneration in SH-SY5Y neuroblastoma cells, extending characterization of beta/A4 toxicity to a human nerve cell line. Human SH-SY5Y cells respond to aggregated beta/A4 with changes in cell shape, membrane blebbing, antigenic modification, loss of attachment to the substrate, and cell death. beta/A4 peptides require aggregation for maximum toxic effects, as cellular degeneration is evoked by aggregated beta/A4 1-42 and 4-41 cysteine but not by monomeric beta/A4 1-40. Aged (pre-aggregated) beta/A4 1-40 also evoked neurodegeneration. Antigenic changes comprise upregulation of Alzheimer's-type tau epitopes, recognized by the PHF-1 and Alz-50 monoclonals. These particular changes in tau support the connectivity between this in vitro model and mechanisms leading to neurodegeneration in Alzheimer's disease. A significant feature of the SH-SY5Y response is that cells must be differentiated before they become sensitive to the degeneration evoked by beta/A4. Signaling pathways leading to beta/A4-evoked neurodegeneration thus are under experimental control, becoming complete only when proliferating cells withdraw from the cell cycle and develop a postmitotic phenotype.
Lambert
M P
MP
Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208.
Stevens
G
G
Sabo
S
S
Barber
K
K
Wang
G
G
Wade
W
W
Krafft
G
G
Snyder
S
S
Holzman
T F
TF
Klein
W L
WL
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D000939:Epitopes / Q000032:analysis; D006801:Humans; D009410:Nerve Degeneration / Q000187:drug effects*; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D011107:Polylysine; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000032:analysis / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D000939:Epitopes; D010446:Peptide Fragments; D016875:tau Proteins; D011107:Polylysine