Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease

Abstract

Inhibition of protein translation is a mode of inducing neuronal apoptosis and neurodegeneration in Alzheimer's disease (AD). Phosphorylation of eukaryotic initiation factor-2α (eIF2α) terminates global protein translation and induces apoptosis. We examined whether this signaling pathway occurs in degenerating neurons of AD. Brain sections from young individuals, age-matched control individuals and AD patients were examined for immunoreactivity of phosphorylated eIF2α by immunohistochemical analysis. While young brain sections did not display and age-matched brain sections have mild immunoreactive positive cells, AD brain sections revealed intense immunoreactivity for phosphorylated eIF2α. Most of the phosphorylated eIF2α immunoreactive positive neurons have high immunoreactivity for phosphorylated tau using AT8 antibody. Also, intense staining of phosphorylated eIF2α is associated vacuoles in degenerating neurons. This phenomenon was also observed for the immunohistochemical staining of phosphorylated PKR (double-stranded RNA-dependent protein kinase), the upstream kinase for eIF2α. Activation of PKR-eIF2α pathway is considered to be pro-apoptotic. In addition, formation of autophagy is regulated by eIF2α kinase. Therefore, it is concluded that phosphorylation of eIF2α is associated with the degeneration of neurons in AD. © 2002 Lippincott Williams & Wilkins.