The participation of activating transcription factor 6 alpha, ATF6α, in Alzheimer’s disease

Background:
Alzheimer’s disease (AD) is the leading cause of dementia in elderly humans worldwide. More than 40million people currently suffer from AD, and this prevalence tends to increase considerably in thecoming decades due to increased longevity. The unfolded protein response (UPR) is an adaptivesignaling mechanism that aims to maintain cell viability under misfolded protein accumulation andendoplasmic reticulum stress. UPR activation is associated with neurodegenerative diseases, such asAD, leading to synaptic loss and neuronal death. A key but understudied branch of the UPR depends onthe activation of transcription factor 6 α (ATF6α). ATF6α was recently proposed as a therapeutical targetin heart disease. Nonetheless, the association between ATF6α signaling and AD remains elusive. Here,we investigated whether dysfunctional ATF6α associates with AD, using both human
post-mortem
braintissues and mouse models.
Method:
ATF6α protein levels were measured in
post-mortem
cerebral cortex from healthy controls (HC) and ADpatients, as well as in the hippocampus of APP/PS1 transgenic mice. Using an online database (Aging,dementia and TBI study from the Allen Institute) ATF6α
mRNA expression was analyzed in HC and ADsubjects.
Result:
Initial results suggest that ATF6α protein levels are reduced in AD patients. Using the Allen Institutedatabase, we also found reduced ATF6α mRNA expression, in relation to the Braak scale of taupathology in the parietal neocortex and hippocampus. Conversely, we found increased ATF6α proteinlevels in the hippocampus of the APP/PS1 transgenic mouse model of amyloid pathology.
Conclusion:
Together, our results indicate that ATF6α may be differentially altered in AD. Further investigation of theATF6α pathway in AD may offer a novel therapeutic perspective for cognitive decline.