Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits

Abstract

Expression of long-lasting synaptic plasticity and long-term memory requires new protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2α subunit (eIF2α). It was reported previously that eIF2α phosphorylation is elevated in the brains of Alzheimer’s disease (AD) patients and AD model mice. Therefore, we determined whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in AD model mice. The genetic deletion of the eIF2α kinase PERK prevented enhanced eIF2α phosphorylation, as well as deficits in protein synthesis, synaptic plasticity, and spatial memory in APP/PS1 AD model mice. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and spatial memory defects displayed in the APP/PS1 mice. Our findings implicate aberrant eIF2α phosphorylation as a novel molecular mechanism underlying AD-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for the treatment of individuals with AD.

Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses

“…Indeed, targeting the PERK-eIF2␣ pathway using GSK6206414, ISRIB, or genetic approaches has been shown to attenuate disease in mouse models of prion and Alzheimer disease (17,18,35,36). One mechanism the authors uncovered for the beneficial actions of PERK inhibition is the restoration of critical synaptic proteins such as SNAP25 and PSD95.…”

“…By targeting ER stress signaling, it may be possible to break this cycle. PERK is a particularly attractive target because it is a key player in ER stress-induced inflammation, and disruption of PERK has been shown to be beneficial in mouse models of Alzheimer disease and prion disease (17,18).…”

Inhibition of AMP-Activated Protein Kinase Signaling Alleviates Impairments in Hippocampal Synaptic Plasticity Induced by Amyloid β

“…3C). Defects in de novo protein synthesis have been linked to synaptic dysfunction in APP/PS1 mice (Ma et al, 2013). To examine the effects of AMPK inhibition on de novo protein synthesis in APP/PS1 mice, we performed SUnSET experiments on hippocampal slices and observed that the levels of newly synthesized proteins in area CA1 were increased by CC, compared with the vehicle control groups (Fig.…”

“…AMPK also regulates protein synthesis, which plays a critical role in consolidating long-lasting synaptic plasticity and longterm memory (Klann and Dever, 2004;Costa-Mattioli et al, 2009), and dysregulated protein synthesis recently was implicated in AD pathogenesis (Ma et al, 2013). Of note, it was shown that AMPK activity is important in maintaining protein synthesis-dependent forms of synaptic plasticity (Potter et al, 2010).…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…Extending this to mammalian cortical neurons showed that treatment by the PERKi inhibitor mitigates risk of death of primary rat cortical neurons expressing TDP-43 (Kim et al 2014). The approach of targeting stress granule formation is a potentially rich area for investigation as stress granule modulation pathways have been implicated in mouse models of Alzheimer's (Ma et al 2013) and prion disease (Moreno et al 2012(Moreno et al , 2013; in the latter case, treatment by the PERKi strikingly mitigates degeneration (Moreno et al 2013). The association of these processes with several different disease models, and perhaps normal memory (Sidrauski et al 2013(Sidrauski et al , 2015Sekine et al 2015), suggests that inhibition of translation via phosphorylation of eIF2a coupled to stress granule formation, may be a unifying pathway common to a number of disease and other situations.…”