title: Fibrillar prion peptide PrP(106-126) treatment induces Dab1 phosphorylation and impairs APP processing and Abeta production in cortical neurons.
abstract: Alzheimer's disease and prion diseases (e.g., Creutzfeldt-Jakob disease) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. However, the intracellular events in prion diseases and their relation with the processing of the amyloid precursor protein (APP) and beta-amyloid generation are unknown. The adaptor protein Dab1 may regulate intracellular trafficking and secretase-mediated proteolysis in APP processing. However, a putative relationship between prion diseases and Dab1/APP interactions is lacking. Thus, we examined, in inoculated animals, whether Dab1 and APP processing are targets of the intracellular events triggered by extracellular exposure to PrP(106-126) peptide. Our in vitro results indicate that PrP(106-126) peptide induces tyrosine phosphorylation of Dab1 by activated members of the Src family of tyrosine kinases (SFK), which implies further Dab1 degradation. We also corroborate these results in Dab1 protein levels in prion-inoculated hamsters. Finally, we show that fibrillar prion peptides have a dual effect on APP processing and beta-amyloid production. First, they block APP trafficking at the cell membrane, thus decreasing beta-amyloid production. In parallel, they reduce Dab1 levels, which also alter APP processing. Lastly, neuronal cultures from Dab1-deficient mice showed severe impairment of APP processing with reduced sAPP secretion and A beta production after prion peptide incubation. Taken together, these data indicate a link between intracellular events induced by exposure to extracellular fibrillar peptide or PrP(res), and APP processing and implicate Dab1 in this link.
authors: Cellular and Molecular Basis of Neurodegeneration and Neurorepair, Department of Cell Biology, University of Barcelona, Spain.
authors: Rosalina
authors: R
authors: Gavín
authors: Jesus
authors: J
authors: Ureña
authors: Alejandra
authors: A
authors: Rangel
authors: Miguel A
authors: MA
authors: Pastrana
authors: Jesús R
authors: JR
authors: Requena
authors: Eduardo
authors: E
authors: Soriano
authors: Adriano
authors: A
authors: Aguzzi
authors: José A
authors: JA
authors: Del Río
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D018622:PrP 27-30 Protein / Q000494:pharmacology; D011247:Pregnancy; D011328:Prions / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C103773:Dab1 protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126); D018622:PrP 27-30 Protein