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.

Fig. (1)

Processing of Amyloid Precursor Protein (APP) by α, β and γ secretases. The proteolytic cleavage in non-amyloidogenic pathway by α secretase within the Aβ sequence and γ secretase resulting in the formation of soluble APP fragments: APPsα, p3 and p7. The APP processing by secretases β and γ in the amyloidogenic pathway leads to the formation of C-terminal APP domain AICD and soluble Aβ37–40 or insoluble Aβ42, which depends on the γ secretase cleaving site. Aβ42 aggregates into amyloid plaques in the brain tissue.

Fig. (2)

Schematic representation of APP point mutations sequence affecting secretase activities. Pathogenic amino acids substitutions, which are identified near or within the APP cleavage site by secretases, shift the APP molecular processing toward the amyloidogenic pathway. That leads to overall increase in total Aβ generation and/or alterations in the ratio of specific Aβ peptides.

Fig. (3)

Three branches of UPR signalling from the Endoplasmatic Reticulum. In response to accumulation unfolded and misfolded proteins within ER lumen that trigger ER stress BiP chaperones release the luminal domain of ER transmembrane transducers such as PERK, IRE1, ATF6. That allows PERK and IRE1 to oligomerise and trans-autophosporylate, which result in their activation. Also ATF6 is regulated by chaperones BiP which hinder its relocation to the Golgi, where it is processed by specific proteases Site-1 (S1P) and Site-2 (S2P) and, as a result, becomes active as a monomeric ATF6N. Activated PERK phosphorylates eIF2α resulting in global translation attenuation apart from selective mRNAs e.g. ATF4. ATF6N, XBP1s and ATF4 translocates to the nucleus where upregulates expression of UPR target gene to restore cells homeostasis.

Fig. (4)

Mechanism of UPR-induced apoptosis in Alzheimer’s disease. Multiple signalling pathways of the UPR are activated by PERK kinase by dissociation of BiP proteins after the accumulation of unfolded proteins within the lumen of the ER. This dissociation causes PERK to undergo homo-oligomerization and trans-autophosphorylation within its cytosolic kinase domain. The activated UPR network results in the phosphorylation of eIF2α and, consequently, in the sustained inhibition of general translation, while it leads to up-regulation of mRNAs BACE1 and ATF4. Long-term stress conditions may induce neuronal death by mitochondrial apoptosis regulated by the family of the anti-apoptotic and pro-apoptotic proteins. This results in neurodegeneration and memory impairment associated with AD.