title: Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila.
abstract: The mechanism of widespread neuronal death occurring in Alzheimer's disease (AD) remains enigmatic even after extensive investigation during the last two decades. Amyloid beta 42 peptide (Abeta(1-42)) is believed to play a causative role in the development of AD. Here we expressed human Abeta(1-42) and amyloid beta 40 (Abeta(1-40)) in Drosophila neurons. Abeta(1-42) but not Abeta(1-40) causes an extensive accumulation of autophagic vesicles that become increasingly dysfunctional with age. Abeta(1-42)-induced impairment of the degradative function, as well as the structural integrity, of post-lysosomal autophagic vesicles triggers a neurodegenerative cascade that can be enhanced by autophagy activation or partially rescued by autophagy inhibition. Compromise and leakage from post-lysosomal vesicles result in cytosolic acidification, additional damage to membranes and organelles, and erosive destruction of cytoplasm leading to eventual neuron death. Neuronal autophagy initially appears to play a pro-survival role that changes in an age-dependent way to a pro-death role in the context of Abeta(1-42) expression. Our in vivo observations provide a mechanistic understanding for the differential neurotoxicity of Abeta(1-42) and Abeta(1-40), and reveal an Abeta(1-42)-induced death execution pathway mediated by an age-dependent autophagic-lysosomal injury.
authors.affiliation: Division of Neuroscience, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Daijun
authors.initials: D
authors.lastname: Ling
authors.forename: Ho-Juhn
authors.initials: HJ
authors.lastname: Song
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Neufeld
authors.forename: Paul M
authors.initials: PM
authors.lastname: Salvaterra
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy; D004331:Drosophila melanogaster; D006801:Humans; D008247:Lysosomes; D009410:Nerve Degeneration / Q000139:chemically induced*; D010446:Peptide Fragments / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments