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Fibrillar prion peptide PrP(106-126) treatment induces Dab1 phosphorylation and impairs APP processing and A beta production in cortical neurons


Gavín, R; Ureña, J M; Rangel, A; Pastrana, M A; Requena, J R; Soriano, E; Aguzzi, A; Del Río, J A (2008). Fibrillar prion peptide PrP(106-126) treatment induces Dab1 phosphorylation and impairs APP processing and A beta production in cortical neurons. Neurobiology of Disease, 30(2):243-254.

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.

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.

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9 citations in Web of Science®
11 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2008
Deposited On:21 Oct 2008 13:25
Last Modified:05 Apr 2016 12:29
Publisher:Elsevier
ISSN:0969-9961
Publisher DOI:10.1016/j.nbd.2008.02.001
PubMed ID:18374587
Permanent URL: http://doi.org/10.5167/uzh-4125

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