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 (Aβ _1–42) is believed to play a causative role in the development of AD. Here we expressed human Aβ _1–42 and amyloid beta 40 (Aβ _1–40) in Drosophila neurons. Aβ _1–42 but not Aβ _1–40 causes an extensive accumulation of autophagic vesicles that become increasingly dysfunctional with age. Aβ _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 Aβ _1–42 expression. Our in vivo observations provide a mechanistic understanding for the differential neurotoxicity of Aβ _1–42 and Aβ _1–40, and reveal an Aβ _1–42-induced death execution pathway mediated by an age-dependent autophagic-lysosomal injury.