Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer’s Disease

Abstract

Recent evidence suggests that the development of Alzheimer’s disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase β (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid β (Aβ) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β-amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.

Differential contributions of ApoE4 and female sex to BACE1 activity and expression mediate Aβ deposition and learning and memory in mouse models of Alzheimer’s disease

“…A further increased BACE1 protein expression in ApoE4/3xTg females may be related to ApoE4 domain interaction induced-endoplasmic reticulum stress ( Zhong et al, 2009 ). The endoplasmic reticulum stress is known to activate the PERK-dependent elF2α phosphorylation, which promotes BACE1 synthesis ( Rozpedek et al, 2015 ).…”

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

“…Nmp4 control of protein translation and movement through the bone cell ER is particularly intriguing since this is a potential promising area for drug target discovery. Several therapeutic strategies and multiple drugs are currently being developed to enhance the adaptive capability of the ER in the service of secretion for numerous diseases including diabetes, cancer, Alzheimer's, and osteoporosis(24,36,40,54,87,91,104). Nmp4 control of metabolic reprogramming may also present therapeutic targets for regulating bone anabolism(48,49,106).…”

Sustained Activation of the Unfolded Protein Response Induces Cell Death in Fuchs' Endothelial Corneal Dystrophy

“…9,10,12 Consequently, targeting the UPR has emerged as a promising therapeutic modality for the treatment of diseases related to accumulation of unfolded or misfolded proteins in the ER. [13][14][15] Our aim in the present study was to investigate the potential involvement of the UPR in FECD as a possible contributor to the underlying pathophysiological mechanism. Here, we have investigated the accumulation of unfolded or misfolded proteins in the corneal endothelium with the goal of detecting any functional links between the UPR and apoptosis of CECs in FECD.…”