Endoplasmic reticulum stress in aged P301L Tau transgenic mice

Abstract

Background: Accumulating evidence indicates that abnormalities in tau protein play a critical role in the pathogenesis of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in pathological processes resulting in neuronal death in AD. However, the potential connection of tau abnormalities and ER stress was not explored. Methods: Immunofluorescence staining of phosphorylated tau (pT231) and ER stress markers PERK and CHOP was performed to determine any colocalization of phosphorylated tau and increased ER-stress markers in aged (22 months old) transgenic mice expressing the P301L mutated form of human tau. Furthermore, Western-blot analysis was used to detect the levels of BiP, one of ER stress markers, and phosphorylation of eIF2α. Results: Immunfluorescence analysis revealed that activation of PERK (increased phosphorylation of PERK) and increased expression of CHOP were observed in hippocampal neurons containing accumulation of phosphorylated tau in the aged transgenic mice. Western-blot analysis revealed that the levels of BiP and phosphorylation of eIF2α were significantly increased in the hippocampus of aged transgenic mice. Conclusions: Our data indicate that in addition to β-amyloid peptide, pathological tau can also induce ER stress, which can be involved in promoting neuronal loss (apoptosis) observed in this transgenic mouse model and AD cases.