1. Restoring synaptic plasticity and memory in mouse models of Alzheimer’s disease by PKR inhibition
- Author
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Kyoung Doo Hwang, Sangmyung Rhee, Sang Jeong Kim, Yong Seok Lee, and Myeong Seong Bak
- Subjects
Male ,0301 basic medicine ,Contextual fear conditioning ,Transgene ,Long-Term Potentiation ,Alzheimer’s disease (AD) ,PKR inhibitor (PKRi) ,Hippocampus ,Mice, Transgenic ,Biology ,lcsh:RC346-429 ,eIF-2 Kinase ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Memory ,Animals ,Amyloid β (Aβ) ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Mice, Inbred ICR ,Long-term potentiation (LTP) ,Amyloid beta-Peptides ,Neuronal Plasticity ,Mechanism (biology) ,Research ,food and beverages ,Long-term potentiation ,Protein kinase R ,Disease Models, Animal ,030104 developmental biology ,Synaptic plasticity ,Phosphorylation ,Object recognition memory ,Psychopharmacology ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - 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. Electronic supplementary material The online version of this article (10.1186/s13041-017-0338-3) contains supplementary material, which is available to authorized users.
- Published
- 2017