Dietary salt, vascular dysfunction, and cognitive impairment

Abstract

Excessive salt consumption is a major health problem worldwide leading to serious cardiovascular events including hypertension, heart disease, and stroke. Additionally, high-salt diet has been increasingly associated with cognitive impairment in animal models and late-life dementia in humans. High-salt consumption is harmful for the cerebral vasculature, disrupts blood supply to the brain, and could contribute to Alzheimer's disease pathology. Although animal models have advanced our understanding of the cellular and molecular mechanisms, additional studies are needed to further elucidate the effects of salt on brain function. Furthermore, the association between excessive salt intake and cognitive impairment will have to be more thoroughly investigated in humans. Since the harmful effects of salt on the brain are independent by its effect on blood pressure, in this review, I will specifically discuss the evidence, available in experimental models and humans, on the effects of salt on vascular and cognitive function in the absence of changes in blood pressure. Given the strong effects of salt on the function of immune cells, I will also discuss the evidence linking salt consumption to gut immunity dysregulation with particular attention to the ability of salt to disrupt T helper 17 (Th17) cell homeostasis. Lastly, I will briefly discuss the data implicating IL-17A, the major cytokine produced by Th17 cells, in vascular dysfunction and cognitive impairment.

Keywords: Cognitive impairment; Endothelial dysfunction; Sodium chloride; Th17 cells.

Figure 1

Effect of HSD on endothelial function. HSD profoundly alters the ability of ECs to produce NO. IL-17A, interleukin-17A; eNOS, endothelial NO synthase; BH4, tetrahydrobiopterin; NALP3, NLR Family Pyrin Domain Containing 3; Cu/Zn SOD, Cu/Zn–superoxide dismutase; O₂^•−, superoxide ion.

Figure 2

Mechanisms by which HSD leads to reduced endothelial NO availability and, in turn, to tau phosphorylation and cognitive impairment. Circulating IL-17A suppresses endothelial NO production by inducing inhibitory phosphorylation of eNOS at Thr⁴⁹⁵. The NO deficit results in reduced calpain nitrosylation in neurons, increased calpain activity, p35 to p25 cleavage, activation of Cdk5, and tau phosphorylation, which is ultimately responsible for cognitive dysfunction. CBF, cerebral blood flow; CDK5, cyclin-dependent kinase 5; Cys-SH, cysteine thiol.

Figure 3

Mechanisms by which HSD increases gut Th17 differentiation. Increased salt (sodium chloride, NaCl) concentration promotes the induction of Th17 cells in the lamina propria of the distal small intestine. The effect is dependent on the activation of the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5) and serum/glucocorticoid-regulated kinase 1 (SGK1). HSD markedly impairs regulatory T cells (T_regs) function further promoting Th17 differentiation. In addition, HSD leads to a reduction in intestinal L. murinus abundance, which, in turn, promotes a Th17 response by suppressing the production of indole metabolites of tryptophan including ILA.