title: Dopamine induces apoptosis in APPswe-expressing Neuro2A cells following Pepstatin-sensitive proteolysis of APP in acid compartments.
abstract: A pathological hallmark of Alzheimer's disease (AD) is the presence within neurons and the interneuronal space of aggregates of β-amyloid (Aβ) peptides that originate from an abnormal proteolytic processing of the amyloid precursor protein (APP). The aspartyl proteases that initiate this processing act in the Golgi and endosomal compartments. Here, we show that the neurotransmitter dopamine stimulates the rapid endocytosis and processing of APP and induces apoptosis in neuroblastoma Neuro2A cells over-expressing transgenic human APP (Swedish mutant). Apoptosis could be prevented by impairing Pepstatin-sensitive and acid-dependent proteolysis of APP within endosomal-lysosomal compartments. The γ-secretase inhibitor L685,458 and the α-secretase stimulator phorbol ester elicited protection from dopamine-induced proteolysis of APP and cell toxicity. Our data shed lights on the mechanistic link between dopamine excitotoxicity, processing of APP and neuronal cell death. Since AD often associates with parkinsonian symptoms, which is suggestive of dopaminergic neurodegeneration, the present data provide the rationale for the therapeutic use of lysosomal activity inhibitors such as chloroquine or Pepstatin A to alleviate the progression of AD leading to onset of parkinsonism.
authors: Department of Health Sciences, Laboratory of Molecular Pathology and Nanobioimaging, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100 Novara, Italy.
authors: Monica
authors: M
authors: Cagnin
authors: Matteo
authors: M
authors: Ozzano
authors: Natascia
authors: N
authors: Bellio
authors: Ilaria
authors: I
authors: Fiorentino
authors: Carlo
authors: C
authors: Follo
authors: Ciro
authors: C
authors: Isidoro
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002219:Carbamates / Q000494:pharmacology; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D010436:Pepstatins / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D010436:Pepstatins; D010703:Phorbol Esters; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D002738:Chloroquine; D053829:Amyloid Precursor Protein Secretases; D002402:Cathepsin D; C031375:pepstatin; D004298:Dopamine