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 Aβ 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 Aβ triggered cleavage of caspase 3 and poly (ADP-ribose) polymerase to cause neuronal apoptosis in rat cortical neurons. On the other hand, Aβ activated autophagy by inducing autophagic vesicle formation and autophagy related gene 12 (ATG12), and up-regulated the lysoso-mal machinery for the degradation of autophagosomes. Moreover, we demonstrated that activation of autophagy by Aβ preceded that of apoptosis, with death associated protein kinase phosphorylation as the potential molecular link. More importantly, under Aβ toxicity, neurons exhibiting high level of autophagosome formation were absent of apoptotic features, and inhibition of autophagy by 3-methylade-nine advanced neuronal apoptosis, suggesting that autophagy can protect neurons from Aβ-induced apoptosis.
Cheung
Yuen-Ting
YT
Laboratory of Neurodegenerative Diseases, Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong, China.
Zhang
Natalie Qishan
NQ
Hung
Clara Hiu-Ling
CH
Lai
Cora Sau-Wan
CS
Yu
Man-Shan
MS
So
Kwok-Fai
KF
Chang
Raymond Chuen-Chung
RC
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C025946:3-methyladenine; D011065:Poly(ADP-ribose) Polymerases; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D053148:Caspase 3; D000225:Adenine