Caspase-1/IL-1\u03b2 represses membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1 in Alzheimer\u2019s disease

Xunhu Gu,Xu Liu,Hanjun Wu,Wei Wang,Lijun Xu,Yuqin Xie

doi:10.1186/s10020-021-00273-8

Abstract

BackgroundAlzheimer's disease is a neurodegenerative disease. Previous study has reported that caspase-1/IL-1β is closely associated with Alzheimer's disease. However, the biological role of caspase-1/IL-1β in Alzheimer's disease has not been fully elucidated. This study aimed to explore the mechanism of action of caspase-1/IL-1β in Alzheimer's disease.MethodsMouse hippocampal neurones were treated with Aβ1-42 to induce Alzheimer's disease cell model. APP/PS1 mice and Aβ1-42-induced hippocampal neurones were treated with AC-YVAD-CMK (caspase-1 inhibitor). Spatial learning and memory ability of mice were detected by morris water maze. Flow cytometry, TUNEL staining, Thioflavin S staining and immunohistochemistry were performed to examine apoptosis and senile plaque deposition. Enzyme linked immunosorbent assay and western blot were performed to assess the levels of protein or cytokines. Co-Immunoprecipitation was performed to verify the interaction between Stargazin and GluA1.ResultsAC-YVAD-CMK treatment improved spatial learning and memory ability and reduced senile plaque deposition of APP/PS1 mice. Moreover, AC-YVAD-CMK promoted membrane transport of GluA1 in APP/PS1 mice. In vitro, Aβ1-42-induced hippocampal neurones exhibited an increase in apoptosis and a decrease in the membrane transport of GluA1, which was abolished by AC-YVAD-CMK treatment. In addition, Stargazin interacted with GluA1, which was repressed by caspase-1. Caspase-1/IL-1β inhibited membrane transport of GluA1 by inhibiting the interaction between Stargazin and GluA1.ConclusionsOur data demonstrate that caspase-1/IL-1β represses membrane transport of GluA1 by inhibiting the interaction between Stargazin in Alzheimer's disease. Thus, caspase-1/IL-1β may be a target for Alzheimer's disease treatment.

Highlights

Our preliminary experiments have found that inhibition of caspase-1 enhances the surface expression of GluA1 in the hippocampus of APP/PS1 mice, suggesting that up-regulation of caspase-1 may participate in regulating membrane transport disorder of amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA) receptor
The number of platform location crosses of APP/PS1 mice was less than Wild type (WT) mice, while AC-YVAD-CMK treatment significantly enhanced the number of platform location crosses of APP/PS1 mice (Fig. 1b)
APP/PS1 mice displayed an increase of senile plaque deposition in the hippocampal tissues, which was effectively reduced by AC-YVAD-CMK treatment (Fig. 1c, d)

Summary

Introduction

Previous study has reported that caspase-1/IL-1β is closely associated with Alzheimer’s disease. The main pathological features of Alzheimer’s disease are the deposition of amyloid β-protein (Aβ) in the brain, neurofibrillary tangles, synaptic dysfunction and neuron loss (Kenney 2018). Abnormal hippocampal synaptic plasticity has been considered as a key biological basis for cognitive dysfunction in Alzheimer’s disease (Peineau et al 2018). Accumulation studies have shown that abnormal AMPA receptor trafficking is an important feature of synaptic damage, and is closely related to synaptic plasticity and cognitive function in Alzheimer’s disease (Guntupalli et al 2016; Jurado 2017). The study of Chang et al has shown that the surface expression of GluA1 is down-regulated, and the AMPA receptor current is significantly reduced in the hippocampus of Alzheimer’s disease mice (Chang 2006)

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