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

Abstract

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

Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

“…This reinforces previously reported microarray data in N2a cells [65] and PrP C mutant mice at younger stages compared with adults (2-3 months) [72][73][74]. However, these observations are partially in contrast with some recently published results, using human neuroblastoma [75] and HEK293 cells [74]. In these studies, forced PrP C expression in transfected cells with low expression levels of endogenous PrP C decreased total tau protein levels [75].…”

“…However, these observations are partially in contrast with some recently published results, using human neuroblastoma [75] and HEK293 cells [74]. In these studies, forced PrP C expression in transfected cells with low expression levels of endogenous PrP C decreased total tau protein levels [75].…”

“…In fact, it has been proposed that PrP C suppresses tau transcription, probably though modulation of the Fyn pathway [75]. However when we crossed APP/PS1 mice with a mouse model of tau overexpression under a -actin promoter, reduction of PrP C levels by siRNA induced increased presence of both endogenous (regulated by tau promoter) and exogenous tau-GFP (regulated by -actin promoter) (Fig.…”

New light on prions: putative role of co-operation of PrPc and Aβ proteins in cognition

“…Phosphorylated Fyn level increased in a dose-dependent manner 2 hours after Aβ oligomer treatment and interestingly it became decreased 1 day after this treatment. Surprisingly, the murine PrP c M128V, which correspond with the high AD risk polymorphic human PrP c M129V [74] allele was able to bind Aβ oligomers, but it was unable to reverse the tau reduction [13]. This may be another explanation why this polymorphism was associated with lower IQ and white matter reduction in the study mentioned earlier in this article.…”

“…[13,47], and also Lar son and Lesne [48]) suggest that confounding results about PrP c -mediated impairments, as those described previously, may be attributed only to a subset of Aβ oligomers that are mediated through PrP c . For example, no dependence in LTP impairments in studies of Calella et al [11] may be a result of low levels of Aβ dimers in young aged Tg-mice.…”