The complex PrPc-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease

Megan Larson, Mathew A. Sherman, Fatou Amar, Mario Nuvolone, Julie A. Schneider, David A. Bennett, Adriano Aguzzi, Sylvain E. Lesné

Research output: Contribution to journalArticlepeer-review

217 Scopus citations

Abstract

Amid controversy, the cellular form of the prion protein PrPc 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.

Original languageEnglish (US)
Pages (from-to)16857-16871
Number of pages15
JournalJournal of Neuroscience
Volume32
Issue number47
DOIs
StatePublished - Nov 21 2012

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