Emerging roles of ER stress in the aetiology and pathogenesis of Alzheimers disease.


Alzheimer’s disease (AD) is a progressive neurodegenerative disease character-ized by synaptic dysfunction and accumulation of abnormal aggregates formedby amyloid-bpeptides or phosphorylated tau proteins. Accumulating evidencesuggests that alterations in the buffering capacity of the proteostasis networkare a salient feature of AD. The endoplasmic reticulum (ER) is the main com-partment involved in protein folding and secretion and is drastically affectedin AD neurons. ER stress triggers the activation of the unfolded proteinresponse (UPR), a signal transduction pathway that enforces adaptive pro-grams to recover homeostasis or trigger apoptosis of irreversibly damagedcells. Experimental manipulation of specific UPR signaling modules in preclin-ical models of AD has revealed a key role of this pathway in regulating proteinmisfolding and neurodegeneration. Recent studies suggest that the UPR alsoinfluences synaptic plasticity and memory through ER stress-independentmechanisms. Consequently, targeting of the UPR in AD is emerging as aninteresting therapeutic approach to modify the two pillars of AD, protein mis-folding and synaptic failure. Here, we review the functional role of ER stresssignaling in AD, discussing the complex involvement of the pathway in con-trolling neuronal survival, the amyloid cascade, neurodegeneration and synap-tic function. Recent intervention efforts to target the UPR withpharmacological and gene therapy strategies are also discussed

Gerakis Y., Hetz C.

The FEBS Journal (FEBS J)

marzo 01, 2018

DOI: 10.1111/febs.14332

Investigador BNI: Claudio Hetz