Levels of activating transcription factor 6 alpha (ATF6α) in Alzheimer’s disease

Abstract Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. More than 40 million people currently suffer from AD, and such prevalence tends to increase considerably in the coming decades due to increased human longevity. Nonetheless, despite intense research efforts, no therapy has yet proven effective in attenuating or reversing the progression of AD. The unfolded protein response (UPR) is an adaptive signaling mechanism that aims to maintain cell viability under protein folding stress. The accumulation of misfolded proteins is associated with several neurodegenerative diseases, such as AD, leading to synaptic loss and neuronal death. UPR activation depends on stress sensors such as ATF6α (activating transcription factor 6 α). Recently, ATF6α factor gained importance as a therapeutical target in some disorders and pharmacological activation of this pathway has already been shown to be protective in heart disease. Nonetheless, the association between the ATF6α pathway and AD is not fully understood yet. Here we investigated whether dysfunctional ATF6α associates with AD. Method ATF6α protein levels were measured in postmortem tissue from the cerebral cortex and in hippocampus of APP/PS1 transgenic mouse model of amyloid patholy by western blotting. ATF6α mRNA expression was analysed using an online database (Aging, dementia and TBI study from the Allen Institute. Result Initial results using postmortem tissue from the cerebral cortex suggested that ATF6α protein levels are reduced in AD patients. Using an online database (Aging, dementia and TBI study from the Allen Institute), we found reduced ATF6α mRNA expression, in relation to the Braak scale of tau pathology in the parietal neocortex and hippocampus. Conversely, we found increased ATF6α protein levels in the hippocampus of APP/PS1 transgenic mouse model of amyloid pathology. Conclusion Together, our initial results suggest that ATF6α may be differentially altered in AD. Further investigation of the ATF6α pathway in AD may offer a novel therapeutic perspective for cognitive decline.