SP3-Mediated Transcriptional Activation of GRIK1 is Involved in Alzheimer's Disease-Induced Cognitive Decline by Inducing Inflammasome Activation in Microglia.
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Abstract
GRIK1 has been identified to suppress the activation of NLRP3 inflammasome. The present study investigated the damaging effect of GRIK1 on Alzheimer's disease (AD), the most common neurodegenerative disease, by focusing on inflammasome. APP-PS1 mice were subjected to a Y-maze test and a Morris water maze test. APP-PS1 mice with GRIK1 knockdown were constructed using adeno-associated virus, and the effects of GRIK1 knockdown on the NLRP3 inflammasome activation in microglia of brain tissues of APP-PS1 mice were analyzed. Mouse primary microglia BV2 was induced by LPS, and Western blot, flow cytometry, and ELISA were performed. GRIK1 was significantly elevated in the brain tissues of APP-PS1 mice. GRIK1 knockdown inhibited the neuronal damage and NLRP3 neuroinflammation in the brain tissues and improved cognitive dysfunction of APP-PS1 mice. Knockdown of GRIK1 inhibited activation of NLRP3 inflammasome in BV2 cells. SP3 was upregulated in the brain tissues of APP-PS1 mice, and SP3 promoted GRIK1 transcription by binding to its promoter. Overexpression of GRIK1 reversed the mitigating effect of knockdown of SP3 on cognitive dysfunction and NLRP3 activation in APP-PS1 mice. Overall, our results revealed that SP3-induced GRIK1 transcription potentiates NLRP3 inflammasome activation in microglia, leading to cognitive dysfunction in AD.
期刊介绍：
NeuroMolecular Medicine publishes cutting-edge original research articles and critical reviews on the molecular and biochemical basis of neurological disorders. Studies range from genetic analyses of human populations to animal and cell culture models of neurological disorders. Emerging findings concerning the identification of genetic aberrancies and their pathogenic mechanisms at the molecular and cellular levels will be included. Also covered are experimental analyses of molecular cascades involved in the development and adult plasticity of the nervous system, in neurological dysfunction, and in neuronal degeneration and repair. NeuroMolecular Medicine encompasses basic research in the fields of molecular genetics, signal transduction, plasticity, and cell death. The information published in NEMM will provide a window into the future of molecular medicine for the nervous system.
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