The Complex PrPc-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease

Amid controversy, the cellular form of the prion protein PrPc has been proposed to mediate oligomeric amyloid-beta (A beta)-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by A beta oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble A beta activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble A beta binds to PrPc 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 A beta from binding to PrPc, we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric A beta in vitro. Finally, we showed that gene dosage of Prnp regulates A beta-induced Fyn/tau alterations. Together, our findings identify a complete signaling cascade linking one specific endogenous A beta oligomer, Fyn alteration, and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer's disease.