Biochemical pathway linking HSV1 infection and AD.
Despite the viral ability to circumvent host defensive mechanisms, including PKR activation, HSV1 activates PKR in vitro and in vivo. Activated PKR increases eIF2-alpha phosphorylation levels, leading to BACE1 translation de-repression, BACE1 protein up-regulation and Aß production (left track; continuous line). In the right track (dotted line) we present the pharmacological and biological tools that we used to study this pathway: poly (I∶C), to mimic the effect of viral dsRNA; a specific imidazolo-oxindole compound that acts as a potent PKR inhibitor; and a 5′UTR-luc reporter construct used for the evaluation of the translational effect exerted by the PKR-eIF2-alpha pathway over BACE1 5′UTR. Also, we have utilized the PP1c inhibitor salubrinal, which prevents the dephosphorylation of eIF2-alpha.