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Ling, D., Song, H.J., Garza, D., Neufeld, T.P., Salvaterra, P.M. (2009). Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila.  PLoS ONE 4(1): e4201.
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Research paper

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.

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PMC2626277 (PMC) (EuropePMC)
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