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Biochim Biophys Acta ; 1832(12): 2115-26, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23911349

ABSTRACT

The accumulation of ß-amyloid (Aß) peptide in the brain is one of the pathological hallmarks of Alzheimer's disease and is thought to be of primary aetiological significance. In an unbiased genetic screen, we identified puromycin-sensitive aminopeptidase (PSA) as a potent suppressor of Aß toxicity in a Drosophila model system. We established that coexpression of Drosophila PSA (dPSA) in the flies' brains improved their lifespan, protected against locomotor deficits, and reduced brain Aß levels by clearing the Aß plaque-like deposits. However, confocal microscopy and subcellular fractionation of amyloid-expressing 7PA2 cells demonstrated that PSA localizes to the cytoplasm. Therefore, PSA and Aß are unlikely to be in the same cellular compartment; moreover, when we artificially placed them in the same compartment in flies, we could not detect a direct epistatic interaction. The consequent hypothesis that PSA's suppression of Aß toxicity is indirect was supported by the finding that Aß is not a proteolytic substrate for PSA in vitro. Furthermore, we showed that the enzymatic activity of PSA is not required for rescuing Aß toxicity in neuronal SH-SY5Y cells. We investigated whether the stimulation of autophagy by PSA was responsible for these protective effects. However PSA's promotion of autophagosome fusion with lysosomes required proteolytic activity and so its effect on autophagy is not identical to its protection against Aß toxicity.


Subject(s)
Alzheimer Disease/prevention & control , Aminopeptidases/pharmacology , Amyloid beta-Peptides/adverse effects , Brain/metabolism , Drosophila melanogaster/metabolism , Neuroblastoma/prevention & control , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Animals, Genetically Modified , Autophagy , Blotting, Western , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Neuroblastoma/metabolism , Neuroblastoma/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Proteolysis , Puromycin/pharmacology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured
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