Temporal relationship of autophagy and apoptosis in neurons challenged by low molecular weight β-amyloid peptide

Alzheimer's disease (AD) is an aging-related progressive neurodegenerative disorder. Previous studies suggested that various soluble A beta species are neurotoxic and able to activate apoptosis and autophagy, the type I and type II programmed cell death, respectively. However, the sequential and functional relationships between these two cellular events remain elusive. Here we report that low molecular weight A beta triggered cleavage of caspase 3 and poly (ADP-ribose) polymerase to cause neuronal apoptosis in rat cortical neurons. On the other hand, A beta activated autophagy by inducing autophagic vesicle formation and autophagy related gene 12 (ATG12), and up-regulated the lysosomal machinery for the degradation of autophagosomes. Moreover, we demonstrated that activation of autophagy by A beta preceded that of apoptosis, with death associated protein kinase phosphorylation as the potential molecular link. More importantly, under A beta toxicity, neurons exhibiting high level of autophagosome formation were absent of apoptotic features, and inhibition of autophagy by 3-methyladenine advanced neuronal apoptosis, suggesting that autophagy can protect neurons from A beta-induced apoptosis.