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FEBS J. 2018 Mar;285(6):995-1011. doi: 10.1111/febs.14332. Epub 2017 Dec 15.

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease.

Gerakis Y1, Hetz C1,2,3,4,5.

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Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
Buck Institute for Research on Aging, Novato, CA, USA.
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA.
Cellular and Molecular Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.


Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phosphorylated tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network are a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells. Experimental manipulation of specific UPR signaling modules in preclinical models of AD has revealed a key role of this pathway in regulating protein misfolding and neurodegeneration. Recent studies suggest that the UPR also influences synaptic plasticity and memory through ER stress-independent mechanisms. Consequently, targeting of the UPR in AD is emerging as an interesting therapeutic approach to modify the two pillars of AD, protein misfolding and synaptic failure. Here, we review the functional role of ER stress signaling in AD, discussing the complex involvement of the pathway in controlling neuronal survival, the amyloid cascade, neurodegeneration and synaptic function. Recent intervention efforts to target the UPR with pharmacological and gene therapy strategies are also discussed.


UPR ; Alzheimer's disease; ER stress; aging; memory; neurodegeneration; proteostasis


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