title: The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease.
abstract: Amid controversy, the cellular form of the prion protein PrP(c) has been proposed to mediate oligomeric amyloid-β (Aβ)-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Aβ oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble Aβ activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble Aβ binds to PrP(c) at neuronal dendritic spines in vivo and in vitro where it forms a complex with Fyn, resulting in the activation of the kinase. Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrP(c), we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβ in vitro. Finally, we showed that gene dosage of Prnp regulates Aβ-induced Fyn/tau alterations. Together, our findings identify a complete signaling cascade linking one specific endogenous Aβ oligomer, Fyn alteration, and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Larson
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Sherman
authors.forename: Fatou
authors.initials: F
authors.lastname: Amar
authors.forename: Mario
authors.initials: M
authors.lastname: Nuvolone
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Sylvain E
authors.initials: SE
authors.lastname: Lesné
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002850:Chromatography, Gel; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D018621:PrPC Proteins; D016875:tau Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn