Roles of Aβ42 secreted in the lumen of the endoplasmic reticulum played in the disease course of Alzheimer'disease

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It is known that the interaction between AP/APP and tau, the main components of the pathologic lesions of Alzheimer's disease (AD), has significant influence on the pathogenesis of the disease. We have hypothesized that the cytosol domain of APP and the cytosol protein tau interact each other, modulating the phosphorylation of APP at Thr668 and tau at several potential phosphorylation sites. In the present study we focused on C99, the proteolytic product of APP, and examined whether C99 modulates the phosphorylation of tau.In COS7 cells transfected with C99 and tau, the phosphorylations at Thr181 and Thr231 of tau were reduced when co-transfected with C99 compared to that given by transfection of tau without C99. The dephosphorylation-inhibition test with phosphatase inhibitors showed that PP1 is implicated in the dephosphorylation of tau. Negative immunoprecipitation of tau and C99 indicates that tau and C99 do not directly bind each other, providing a possibility that the third agent … More could mediate the interaction of tau and C99. The third agent must bind both tau and APP, and Pin 1 that binds phosphorylated Thr231 of tau and Thr668 of APP could be such a candidate. We examined Pin^<-/->MEF co-transfected with tau and C99. In Pin1^<+/+>MEF and Pin1^<-/->MEF transfected with tau only, the phosphorylation level at Thr181 and Thr231 of tau remained unchanged between the presence and absence of Pin1 expression. In MEF co-transfected with tau and C99, the presence of Pin1 expression increases dephosphorylation of tau, whereas the absence of Pin1 expression not only abrogates dephosphorylation of tau but also increases phosphorylation of tau. Thus tau is dephosphorylated in the concomitant presence of Pin1 and C99, while tau is phosphorylated in the presence of C99 and in the absence of Pin1. These results indicate that C99 and Pin1 are associated with phosphorylation of tau, and such mechanism might underlie the disease course of AD since Pin1 expression is diminished in association of tangle formation. Less