The Nonfibrillar Amyloid β‐Peptide Induces Apoptotic Neuronal Cell Death

Abstract

: The toxicity of the nonaggregated amyloid β-peptide (1-40) [Aβ(1-40)] on the viability of rat cortical neurons in primary culture was investigated. We demonstrated that low concentrations of Aβ 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 Aβ(1-40) peptide with those of several Aβ-peptide domains, comprising the membrane-destabilizing C-terminal domain of Aβ peptide (e.g., amino acids 29-40 and 29-42). These peptides reporduced the effects of the (1-40) peptide, whereas mutant nonfusogenic Aβ peptides and the central region of the Aβ peptide (e.g., amino acids 13-28) had no effect on cell viability. We further demonstrated that the neurotoxicity of the nonaggregated Aβ peptide paralleled a rapid and stable interaction between the Aβ 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 Aβ induces neuronal cell death by either apoptosis and necrosis and that an interaction between the nonfibrillar C-terminal domain of the Aβ peptide and the plasma membrane of cortical neurons might represent an early event in a cascade leading to neurodegeneration.