ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2024
Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 13 citations in OpenAlex.
- Gut microbiota as a modulator of HDAC: insights into Alzheimer's disease treatment.Pharmacological reports : PR · 2026Review
- Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer's Disease Model Mice.Biomolecules · 2026Article
- [Serum from rats with electroacupuncture activates the PI3K/Akt signaling pathway to improve synaptic plasticity in HT22 neurons with oxygen and glucose deprivation].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- MicroRNA-Mediated Regulation of Brain Aging Hallmarks: Implications for Neurodegeneration and Neural Recovery.Brain and behavior · 2026Review
- SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome-lysosome fusion and rescues neurodegeneration in an Alzheimer's disease model.Translational neurodegeneration · 2025Article
- Epigenetic regulation of iron metabolism and ferroptosis in Parkinson's disease: Identifying novel epigenetic targets.Acta pharmacologica Sinica · 2025Review
- Article
- Genome-wide study links cardiometabolic factors to cognition via APOA4-APOA5-ZPR1-BUD13 and other loci in rural Indians.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Histone Deacetylation in Alzheimer's Diseases (AD); Hope or Hype.Cell biochemistry and biophysics · 2025Review
- MEF2C Alleviates Postoperative Cognitive Dysfunction by Repressing Ferroptosis.CNS neuroscience & therapeutics · 2024Article
- A bibliometric analysis of the relationship between traumatic brain injury and Alzheimer's disease (1993-2023).Frontiers in aging neuroscience · 2024Article
- SGK1-HDAC4-HMGB1 signaling pathway in the spinal cord dorsal horn participates in diabetic neuropathic pain.Molecular painArticle
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.
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