Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with deficits in cognition and synaptic plasticity. While accumulation of amyloid β (Aβ) and hyper-phosphorylation of tau are parts of the etiology, AD can be caused by a large number of different genetic mutations and other unknown factors. Considering such a heterogeneous nature of AD, it would be desirable to develop treatment strategies that can improve memory irrespective of the individual causes. Reducing the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) was shown to enhance long-term memory and synaptic plasticity in naïve mice. Moreover, hyper-phosphorylation of eIF2α is observed in the brains of postmortem AD patients. Therefore, regulating eIF2α phosphorylation can be a plausible candidate for restoring memory in AD by targeting memory-enhancing mechanism. In this study, we examined whether PKR inhibition can rescue synaptic and learning deficits in two different AD mouse models; 5XFAD transgenic and Aβ1–42-injected mice. We found that the acute treatment of PKR inhibitor (PKRi) can restore the deficits in long-term memory and long-term potentiation (LTP) in both mouse models without affecting the Aβ load in the hippocampus. Our results prove the principle that targeting memory enhancing mechanisms can be a valid candidate for developing AD treatment.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive deficits and synaptic dysfunction, for which there is currently no effective treatment available
We examined whether PKR inhibitor (PKRi) can reverse the long-term potentiation (LTP) deficit in the hippocampal Schaffer-collateral pathway in 5XFAD mice
We found that PKRi treatment restored the deficit in TBS-induced LTP in hippocampal slices from 5XFAD mice without affecting LTP in wild-type slices (Fig. 2; Average Field excitatory postsynaptic potential (fEPSP) slope, last 10 min: WT, 147.77 ± 2.19%, n = 6 slices from 4 mice; WT and PKRi, Fig. 2 Inhibition of Protein kinase RNA-activated (PKR) restores LTP impairment in 5XFAD mice. a LTP in Schaffer-collateral-CA1 pathway was induced by theta burst stimulation (TBS)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive deficits and synaptic dysfunction, for which there is currently no effective treatment available. APP encodes amyloid β (Aβ) precursor protein, while PSEN1 and PSEN2 encodes presenilin-1 and presenilin, respectively. These proteins are involved in Aβ processing pathway and support a hypothesis that Aβ accumulation in the brain is critical for the. Hwang et al Molecular Brain (2017) 10:57 potentiation (LTP) and long-term memory by reducing ATF4 translation in mice [19]. In addition to eIF2α, the double-stranded RNA-activated protein kinase (PKR), one of eIF2α kinases, is highly phosphorylated in AD brains [7, 11, 20]. Previous studies revealed that either genetic or pharmacological blockage of PKR enhances LTP and memory in mice [22, 23]
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