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Review
. 2014 Apr 16:7:22.
doi: 10.3389/fnmol.2014.00022. eCollection 2014.

Roles of eIF2α kinases in the pathogenesis of Alzheimer's disease

Masuo Ohno  1
Affiliations
Review

Roles of eIF2α kinases in the pathogenesis of Alzheimer's disease

Masuo Ohno. Front Mol Neurosci. .

Abstract

Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of eukaryotic initiation factor-2α (eIF2α). Evidence is accumulating that persistent eIF2α phosphorylation at Ser51 through prolonged overactivation of regulatory kinases occurs in neurodegenerative diseases such as Alzheimer's disease (AD), leading to shutdown of general translation and translational activation of a subset of mRNAs. Recent advances in the development of gene-based strategies and bioavailable inhibitors, which specifically target one of the eIF2α kinases, have enabled us to investigate pathogenic roles of dysregulated eIF2α phosphorylation pathways. This review provides an overview of animal model studies in this field, focusing particularly on molecular mechanisms by which the dysregulation of eIF2α kinases may account for synaptic and memory deficits associated with AD. A growing body of evidence suggests that correcting aberrant eIF2α kinase activities may serve as disease-modifying therapeutic interventions to treat AD and related cognitive disorders.

Keywords: ATF4; Alzheimer’s disease; BACE1; PERK; PKR; amyloid-β; elF2α; learning and memory.

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Figures

FIGURE 1
FIGURE 1
Multiple molecular mechanisms by which dysregulated eIF2α kinase activities may lead to memory deficits and neurodegeneration associated with AD. Four eIF2α kinases become activated in response to diverse cellular stress stimuli. Persistent eIF2α phosphorylation through aberrant activation of these kinases in AD causes the inhibition of general translation, while it activates gene-specific translation of mRNAs such as BACE1 and ATF4.
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