Alzheimer's Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Amyloid-beta (A beta) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). A beta oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, A beta oligomers have been shown to specifically interact with cellular prion protein (PrPC) where the role of PrPC in AD is still not fully understood. To investigate the downstream mechanism of PrPC and A beta oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrPC and studied the effect under A beta oligomer treatment. By Western blotting, we found that PrPC overexpression down-regulated tau protein and A beta oligomer binding alleviated the tau reduction induced by wild type but not M128V PrPC, the high AD risk polymorphic allele in human prion gene. PrPC lacking the A beta oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrPC effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrPC-induced tau reduction and A beta oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated A beta-PrPC-tau signaling. Overall, our results demonstrated that PrPC down-regulated tau via the Fyn pathway and the effect can be regulated by A beta oligomers. Our study facilitated the understanding of molecular mechanisms among PrPC, tau, and A beta oligomers.