Pathogenesis and promising therapeutics of Alzheimer disease through eIF2α pathway and correspondent kinases.

Metabolic Brain Disease
Reza Moradi MajdFarzaneh Rahmani

Abstract

Eukaryotic initiation factor 2 (eIF2α) pathway is overactivated in Alzheimer disease and is probably associated with synaptic and memory deficiencies. EIF2α protein is principally in charge of the regulation of protein synthesis in eukaryotic cells. Four kinases responsible for eIF2α phosphorylation at ser-51 are: General control non-derepressible-2 kinase (GCN2), double-stranded RNA-activated protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI) are the four kinases. They lead to reduced levels of general translation and paradoxical increase of stress-responsive mRNAs expression including the B-secretase (BACE1) and the transcriptional modulator activating transcription factor 4 (ATF4), which in turn accelerates the beta-amyloidogenesis, tau phosphorylation, proapoptotic pathway induction and autophagy elements formation leading to the main pathological hallmarks of AD. Findings suggest that genetic or pharmacological inhibition of correspondent kinases can restore memory and prevent neurodegeneration. This implies that inhibition of eIF2α phosphorylation through respondent kinases is indeed a feasible prospect of clinical application. This review discusses recent therape...Continue Reading

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Citations

Apr 4, 2021·International Journal of Molecular Sciences·Jacques Hugon, Claire Paquet
Sep 23, 2021·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Haili WangYingzhu Chen
Oct 8, 2021·Brain : a Journal of Neurology·Naciye MagusaliDervis A Salih

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Methods Mentioned

BETA
environmental stress
transgenic

Software Mentioned

ISRIB

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