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.