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High-Salt Diet Accelerates Neuron Loss and Anxiety in APP/PS1 Mice Through Serpina3n

Year: 2024

Type: article

Abstract: High salt (HS) consumption is an independent risk factor for neurodegenerative diseases such as dementia, stroke, and cerebral small vessel disease related to cognitive decline. Recently, Alzheimer’s disease-like pathology changes have been reported as consequences of a HS diet in wild-type (wt) mice. However, it has not been revealed how HS diets accelerate the progress of Alzheimer’s disease (AD) in APP/PS1 mice. Here, we fed APP/PS1 mice a HS diet or normal diet (ND) for six months; the effects of the HS/ND on wt mice were also observed. The results of our behavior test reveal that the HS diet exacerbates anxiety, β-amyloid overload, neuron loss, and synapse damage in the hippocampi of APP/PS1 mice; this was not observed in HS-treated wt mice. RNA sequencing shows that nearly all serpin family members were increased in the hippocampus of HS-treated APP/PS1 mice. Gene function analysis showed that a HS diet induces neurodegeneration, including axon dysfunction and neuro-ligand-based dysfunction, and regulates serine protein inhibitor activities. The mRNA and protein levels of Serpina3n were dramatically increased. Upregulated Serpina3n may be the key for β-amyloid aggregation and neuronal loss in the hippocampus of HS-treated APP/PS1 mice. Serpina3n inhibition attenuated the anxiety and increased the number of neurons in the hippocampal CA1(cornu ammonis) region of APP/PS1 mice. Our study provides novel insights into the mechanisms by which excessive HS diet deteriorates anxiety in AD mice. Therefore, decreasing daily dietary salt consumption constitutes a pivotal public health intervention for mitigating the progression of neuropathology, especially for old patients and those with neurodegenerative disease.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms252111731