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Am J Neurodegener Dis 2013;2(4):247-265

Review Article
ER-stress in Alzheimer’s disease: turning the scale?

Kristina Endres, Sven Reinhardt

Department of Psychiatry and Psychotherapy, Clinical Research Group, University Medical Centre Johannes
Gutenberg-University Mainz, Untere Zahlbacher Str. 8, D-55131 Mainz, Germany

Received September 30, 2013; Accepted November 5, 2013; Epub November 29, 2013; Published December 15, 2013

Abstract: Pathogenic mechanisms of Alzheimer’s disease (AD) are intensely investigated as it is the most common
form of dementia and burdens society by its costs and social demands. While key molecules such as A-beta peptides
and tau have been identified decades ago, it is still enigmatic what drives the disease in its sporadic manifestation.
Synthesis of A-beta peptides as well as phosphorylation of tau proteins comprise normal cellular functions and occur
in principle in the healthy as well as in dementia-affected persons. Dyshomeostasis of Amyloid Precursor Protein
(APP) cleavage, energy metabolism or kinase/phosphatase activity due to stressors has been suggested as a trigger
of the disease. One way for cells to escape stress based on dysfunction of ER is the unfolded protein response - the
UPR. This pathway is composed out of three different routes that differ in proteins involved, targets and consequences
for cell fate: activation of transmembrane ER resident kinases IRE1-alpha and PERK or monomerization of membrane-
anchored activating transcription factor 6 (ATF6) induce activation of versatile transcription factors (XBP-1, eIF2-
alpha/ATF4 and ATF6 P50). These bind to specific DNA sequences on target gene promoters and on one hand
attenuate general ER-prone protein synthesis and on the other equip the cell with tools to de-stress. If cells fail in
stress compensation, this signaling also is able to evoke apoptosis. In this review we summarized knowledge on how
APP processing and phosphorylation of tau might be influenced by ER-stress signaling. In addition, we depicted the
effects UPR itself seems to have on molecules closely related to AD and describe what is known about UPR in AD
animal models as well as in human patients. (AJND1309005).

Keywords: Alzheimer’s disease, secretases, APP, tau, unfolded protein response, calcium homeostasis, autophagy,
apoptosis

Address correspondence to: Dr. Kristina Endres, Department of Psychiatry and Psychotherapy, Clinical Research
Group, University Medical Centre Johannes Gutenberg-University Mainz, Untere Zahlbacher Str. 8, D-55131 Mainz,
Germany. Tel: 49-06131-172133; Fax: 49-06131-176690; E-mail: kristina.endres@unimedizin-mainz.de