Elsevier

Brain Research Bulletin

Volume 141, July 2018, Pages 72-78
Brain Research Bulletin

Review
PERK as a hub of multiple pathogenic pathways leading to memory deficits and neurodegeneration in Alzheimer’s disease

https://doi.org/10.1016/j.brainresbull.2017.08.007Get rights and content

Highlights

  • PERK, an eIF2α kinase, is overly activated in Alzheimer’s disease (AD).

  • Fine-tuning of eIF2α phosphorylation is essential for learning and memory in health.

  • Dysregulated PERK mediates memory deficits and neurodegeneration in mouse models of AD.

  • PERK also plays key roles as an upstream regulator of both β-amyloidosis and tauopathy.

  • Blocking PERK-eIF2α pathway may provide symptomatic benefits and disease modification.

Abstract

Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of eukaryotic initiation factor-2α (eIF2α). In the brain, eIF2α is a hub for controlling learning and memory function and for maintaining neuronal integrity in health and disease. Among four eIF2α kinases, PERK is emerging as a key regulator for memory impairments and neurodegeneration in Alzheimer’s disease (AD). Genetic and pharmacological manipulations of PERK-eIF2α signaling have revealed that the overactivation of this pathway is not a mere consequence of the neurodegenerative process but play critical roles in AD pathogenesis and the occurrence of memory deficits. This review provides an overview of recent progress in animal model studies, which demonstrate that dysregulated PERK accounts for memory deficits and neurodegeneration not only as a detrimental mediator downstream of β-amyloidosis and tauopathy but also as an important determinant upstream of both pathogenic mechanisms in AD. A therapeutic perspective is also discussed, in which interventions targeting the PERK-eIF2α pathway are expected to provide multiple beneficial outcomes in AD, including enhanced mnemonic function, neuroprotection and disease modification.

Introduction

Phosphorylation of the α subunit of eukaryotic initiation factor-2 (eIF2α) controls global protein synthesis rates by inhibiting translation at the level of initiation. Distinct stress conditions activate different eIF2α kinases that converge on phosphorylating Ser51 in eIF2α; in brief, double-stranded RNA-activated protein kinase (PKR) responding to viral infection, PKR-like endoplasmic reticulum kinase (PERK) associated with the unfolded protein response (UPR), general control nonderepressible-2 kinase (GCN2) that is activated during amino acid starvation, and heme-regulated inhibitor kinase (HRI) in response to heme deficiency. This collection of cytoprotective signaling pathways is termed the integrated stress response (ISR) that allows cells to cope with a variety of stresses. Among four ISR pathways, recent investigations increasingly implicate dysregulated PERK signaling as the common underlying mechanism of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and frontotemporal dementia (Bell et al., 2016, Hetz and Mollereau, 2014). PERK-dependent phosphorylation of eIF2α upon the accumulation of misfolded and aggregated protein is known to compose one of the three UPR branches, inducing rapid attenuation of further protein synthesis and thereby providing a protective mechanism that acts to restore protein homeostasis (proteostasis) (Hoozemans et al., 2005, Lee et al., 2010). Meanwhile, sustained eIF2α phosphorylation and the consequent prolonged repression of global protein synthesis, which occur under chronic disease or severe stress conditions (Erguler et al., 2013), are thought to lead to neurodegeneration and memory deficits. Accordingly, it has been demonstrated that the exposure to misfolded proteins such as amyloid-β (Aβ) and tau, the constituents of two hallmark AD pathologies (plaques and tangles, respectively), overly activates the PERK-eIF2α phosphorylation pathway in transgenic mouse models of β-amyloidosis (Devi and Ohno, 2010, Devi and Ohno, 2013a, Devi and Ohno, 2013b, Devi and Ohno, 2014, Kang et al., 2013, Ma et al., 2013, Page et al., 2006) and tauopathy (Abisambra et al., 2013, Radford et al., 2015). More importantly, genetic and pharmacological manipulations of PERK signaling have revealed multiple mechanisms in which the overactivation of PERK-eIF2α pathways is a hub for the progression of AD and related memory deficits (Fig. 1) (Devi and Ohno, 2014, Ma et al., 2013, Radford et al., 2015). The dysregulated PERK branch of UPR has recently emerged as an attractive therapeutic target because of its unique roles in affecting mnemonic processing, causing neurodegeneration and contributing to AD pathogenesis. In this article, I review recent findings that indicate that excessively activated PERK signaling is involved not only in downstream mechanisms mediating memory defects associated with β-amyloidosis and tauopathy but also in upstream events accelerating the development of both hallmark pathologies in AD. I also discuss a therapeutic perspective in which small-molecule drugs targeting the PERK-eIF2α pathway may represent novel memory-facilitating, neuroprotective, and disease-modifying interventions for AD.

Section snippets

eIF2α phosphorylation, synaptic plasticity and memory function

eIF2 consists of three subunits (α, β and γ) and binds GTP and Met-tRNAiMet (initiator methionyl-tRNA) to form a ternary complex, which delivers the initiator tRNA to the 40S ribosomal subunit. Exchange of GDP for GTP on the γ subunit is catalyzed by eIF2B, a guanine nucleotide exchange factor that is required to replenish the active GTP-bound form of eIF2 complex for a new round of translational initiation. Phosphorylation of the eIF2α subunit at Ser51 suppresses general translation

PERK, UPR and AD

The UPR is a protective cellular response in health that is induced by endoplasmic reticulum (ER) stress, aiming to reduce unfolded protein load and restore protein homeostasis. The UPR has three branches, in which the accumulation of misfolded proteins activates respective signaling cascades through PERK, inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6). The first response to ER stress is to attenuate further protein synthesis until the unfolded protein backlog

PERK signaling and memory deficits in β-amyloidosis

To directly address whether the overactivated PERK-eIF2α pathway may contribute to memory impairments in the context of AD, recent studies including ours have explored the functional consequences of targeting PERK activity in transgenic mouse models (Ohno, 2014). By crossing forebrain-specific PERK knockout mice with APP/PS1 mice, Ma et al. (2013) showed that PERK deletion prevents hippocampal eIF2α phosphorylation and memory impairments, as assessed by the hippocampus-dependent spatial

PERK signaling and memory deficits in tauopathy

Tauopathy, another hallmark of AD, also implicates overactivation of the UPR including PERK signaling pathway. PERK dysregulation is closely associated with hyperphosphorylated tau in pretangle neurons during the early stage of disease (Hoozemans et al., 2009, Nijholt et al., 2012). The pathogenic roles of PERK have been addressed, using the rTg4510 mouse model of tauopathy that overexpresses the human mutant tau (P301L) and recapitulates overly activated PERK-eIF2α pathway (Abisambra et al.,

PERK-eIF2α signaling as a therapeutic target for memory deficits in AD

The beneficial effects of pharmacological as well as genetic interventions of the PERK-eIF2α pathway in mouse models of β-amyloidosis and tauopathy provide a proof-of-concept for the therapy with small-molecule PERK inhibitors that show excellent selectivity and bioavailability in vivo (Axten et al., 2012, Moreno et al., 2013). However, it is important to note that PERK−/− mice show early postnatal lethality with hyperglycemia because of inadequate insulin associated with pancreatic islet cell

Conclusion

It is becoming increasingly apparent that the aberrant activation of PERK-dependent eIF2α phosphorylation pathway found in AD plays central roles in inducing multiple pathogenic mechanisms that underlie memory deficits and neurodegeneration (Fig. 1). First, pharmacological and genetic interventions of this pathway are not only neuroprotective through the inhibition of translational repression but also directly memory-improving via blocking ATF4-mediated CREB dysfunction. These detrimental

Conflict of interest

The author declares no conflict of interest.

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