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

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 <i>APP</i>/<i>PS1</i> mice. Here, we fed <i>APP</i>/<i>PS1</i> 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 <i>APP</i>/<i>PS1</i> mice; this was not observed in HS-treated wt mice. RNA sequencing shows that nearly all <i>serpin</i> family members were increased in the hippocampus of HS-treated <i>APP</i>/<i>PS1</i> 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 <i>Serpina3n</i> were dramatically increased. Upregulated Serpina3n may be the key for β-amyloid aggregation and neuronal loss in the hippocampus of HS-treated <i>APP</i>/<i>PS1</i> mice. Serpina3n inhibition attenuated the anxiety and increased the number of neurons in the hippocampal CA1(cornu ammonis) region of <i>APP</i>/<i>PS1</i> 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.