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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.
FlyBase ID
FBrf0206549
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC2626277 (PMC) (EuropePMC)
Related Publication(s)
Note

A central role for autophagy in Alzheimer-type neurodegeneration.
Ling and Salvaterra, 2009, Autophagy 5(5): 738--740 [FBrf0215328]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    PLoS ONE
    Title
    PLoS ONE
    Publication Year
    2006-
    ISBN/ISSN
    1932-6203
    Data From Reference
    Alleles (6)
    Genes (5)
    Human Disease Models (1)
    Transgenic Constructs (5)