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The Role of PKR as a Potential Target for Treating Systemic Inflammation Triggered Neuroinflammation, Tau Phosphorylation and Cognitive Dysfunctions
Author(s) -
Cheng WaiYin,
Ho YuenShan,
Chang Raymond ChuenChung
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.058461
Subject(s) - neuroinflammation , inflammation , laparotomy , morris water navigation task , systemic inflammation , cognitive decline , protein kinase r , medicine , kinase , immunology , endocrinology , protein kinase a , biology , microbiology and biotechnology , surgery , hippocampus , dementia , disease , mitogen activated protein kinase kinase
Background Systemic inflammation has been linked to neuroinflammation and the progression of neurodegenerative diseases. Double‐stranded RNA‐dependent protein kinase (PKR) is a key signaling molecules that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and formation of inflammasomes. This study aims at investigating whether PKR can be a pharmacological target to prevent both systemic inflammation‐triggered neuroinflammation, tau phosphorylation and cognitive dysfunctions. Method Laparotomy, a non‐bacterial endotoxin mouse model, is adopted to address the systemic inflammation triggered by surgery. Male wild‐type C57BL/6J and PKR‐KO mice were randomly divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Expression of mRNA for cytokines and tau protein phosphorylation in different tissues was examined after laparotomy by quantitative RT‐PCR and western blot analysis respectively. Behavioral tests were also performed to examine the effects of laparotomy on cognitive functions. Result We have shown that laparotomy induced peripheral inflammation and neuroinflammation in male C57BL/6J mice. By genetic knockout of PKR in mice, it potently downregulated the increased IL‐1 expression induced by laparotomy in both the liver and frontal cortex at 4 h and day 1 after laparotomy. Meanwhile, knockout of PKR significantly reduced the laparotomy induced tau protein phosphorylation (AT8 and pS416) in the frontal cortex. Furthermore, in wild type mice, cognitive impairment was observed following laparotomy in terms of the decline in problem‐solving abilities, impaired short‐term and long term memory in the puzzle box test; reduced recognition memory with lower discrimination index in the novel object recognition test; and impaired spatial working memory with the reduced percentage of alteration in the spontaneous Y‐maze; while for PKR‐KO mice, cognitive flexibility, short‐term and long term memory recognition memory remained intact after laparotomy. Conclusion This study reveals that genetic knockout of PKR in mice could attenuate laparotomy induced systemic inflammation, neuroinflammation, abnormal tau phosphorylation and cognitive impairment.Further studies will be performed to examine the effect of knockout of PKR in macrophages and cholinergic neurons on systemic inflammation, neuroinflammation and cognitive functions. Acknowledgement: The study is supported by General Research Fund (17123217) to RCCC.