Beta-amyloid induces apoptosis in human-derived neurotypic SH-SY5Y cells.
Alzheimer's disease is primarily characterized by neurofibrillary tangles, senile plaques, and neurodegeneration. The major component of senile plaques is the beta-amyloid peptide (beta A4), which has been shown to be toxic to neurons in vitro. To date, the mechanism of beta A4-induced neurotoxicity has not been determined in human-derived neurons. In this report, we present evidence that programmed cell death, or apoptosis, is involved in the neurotoxic activity of beta A41-40 and beta A425-35 in the human-derived neurotypic cell line SH-SY5Y cells. The evidence for beta A4-induced apoptosis includes: (1) labeling of cell nuclei for DNA nicked ends; (2) morphological changes in ultrastructure that are consistent with apoptosis (shrunken cells with pyknotic nuclei); (3) DNA laddering which can be blocked by aurintricarboxylic acid (ATA), an inhibitor of apoptosis; and (4) marginal release of intracellular lactate dehydrogenase (LDH), an indicator of necrosis. These results suggest that apoptosis is the major event involved in beta A4-induced cytotoxicity in SH-SY5Y cells. A variety of reagents were tested to determine their activities against beta A4-induced DNA laddering. Nerve growth factor and free radical scavengers were inactive in this system. While ATA blocked DNA laddering resulting from either beta A4 or okadaic acid treatment, Congo red specifically attenuated only beta A4-induced DNA fragmentation. These results suggest that compounds which bind fibrillar beta-peptides can protect this human neurotypic cell line against apoptosis induced by beta A4.
Li
Y P
YP
Institute for Dementia Research, Bayer Corporation, West Haven, CT 06516, USA.
Bushnell
A F
AF
Lee
C M
CM
Perlmutter
L S
LS
Wong
S K
SK
D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D003224:Congo Red; D006801:Humans; D008854:Microscopy, Electron; D009336:Necrosis; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D004396:Coloring Agents; D010446:Peptide Fragments; D003224:Congo Red