The nonfibrillar amyloid beta-peptide induces apoptotic neuronal cell death: involvement of its C-terminal fusogenic domain.
The toxicity of the nonaggregated amyloid beta-peptide (1-40) [A beta(1-40)] on the viability of rat cortical neurons in primary culture was investigated. We demonstrated that low concentrations of A beta peptide, in a nonfibrillar form, induced a time- and dose-dependent apoptotic cell death, including DNA condensation and fragmentation. We compared the neurotoxicity of the A beta(1-40) peptide with those of several A beta-peptide domains, comprising the membrane-destabilizing C-terminal domain of A beta peptide (e.g., amino acids 29-40 and 29-42). These peptides reproduced the effects of the (1-40) peptide, whereas mutant nonfusogenic A beta peptides and the central region of the A beta peptide (e.g., amino acids 13-28) had no effect on cell viability. We further demonstrated that the neurotoxicity of the nonaggregated A beta peptide paralleled a rapid and stable interaction between the A beta peptide and the plasma membrane of neurons, preceding apoptosis and DNA fragmentation. By contrast, the peptide in a fibrillar form induced a rapid and dramatic neuronal death mainly through a necrotic pathway, under our conditions. Taken together, our results suggest that A beta induces neuronal cell death by either apoptosis and necrosis and that an interaction between the nonfibrillar C-terminal domain of the A beta peptide and the plasma membrane of cortical neurons might represent an early event in a cascade leading to neurodegeneration.
Pillot
T
T
INSERM U-505, Institut des Cordeliers, Paris, France.
Drouet
B
B
Queillé
S
S
Labeur
C
C
Vandekerchkhove
J
J
Rosseneu
M
M
Pinçon-Raymond
M
M
Chambaz
J
J
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)