In keeping with our GEITP gene-environment interactions theme, this topic concerns interactions between “dietary salt” as the environment, and each person’s genome or genetic susceptibility as the genes. Vascular risk factors — including excessive salt consumption — have long been associated with cerebrovascular diseases and cognitive impairment (when someone has problems remembering, learning new things, concentrating, or making decisions that affect his everyday life). A diet rich in salt is an independent risk factor for stroke and dementia.
A high-salt diet (HSD) has been linked to cerebral small vessel disease that underlies vascular cognitive impairment, a condition associated with blood vessel endothelial dysfunction and impaired cerebral blood flow (CBF). In mice, HSD induces cognitive dysfunction by targeting cerebral microvasculature through a gut-initiated adaptive immune response mediated by TH17 lymphocytes; the resulting increases in circulating interleukin-17 (IL17) — lead to inhibition of endothelial nitric oxide synthase (eNOS), and diminished vascular production of nitric oxide (NO), which, in turn, impairs endothelial vasoactivity which can lower CBF by ~25%.
However, it remains unclear how lowered blood flow (hypoperfusion) — resulting from an HSD or other vascular risk factors — might lead to impaired cognition. The prevailing view is that hypoperfusion compromises delivery of O2 (diatomic oxygen) and glucose to energy-demanding brain regions involved in cognition. However, the relatively small decrease in CBF associated with an HSD in mice, and vascular cognitive impairment in humans, does not seem to be sufficient to impair cognitive function; this suggests that
vascular factors — beyond perfusion of blood throughout the brain — are involved.
Excessive phosphorylation of the microtubule-associated protein tau promotes formation of insoluble tau aggregates, which are
thought to mediate neuronal dysfunction and cognitive impairment in Alzheimer disease and other “tau-opathies.” Therefore, authors [see attached article] investigated whether tau accumulation — rather than brain hypoperfusion — contributes to cognitive dysfunction that is induced by an HSD.
First, authors investigated whether an HSD induces phosphorylation of tau. Mice were fed a normal diet or an HSD [4% or 8% sodium chloride (NaCl) — a commonly used model of excessive dietary salt corresponding to an 8–16-fold increase in salt content compared to regular mouse chow]. An HSD (8% NaCl) induced a sustained increase in phosphorylated tau (detected by AT8 antibodies) in several specific regions of the brain. Authors found neither neuronal nor white-matter damage — nor significant changes in astrocytes, microglia/macrophages or pericytes. However, increased phosphorylated tau (detected by antibodies) was observed in the neocortex of mice fed with the 4% HSD.
Thus, dietary salt was found in mice to enhance phosphorylation of tau — followed by cognitive dysfunction; authors subsequently showed these effects are prevented by restoring eNOS production. NO deficiency appears to lower neuronal calpain nitrosylation, resulting in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin-dependent kinase. Salt-induced cognitive impairment was not observed in tau-null mice, nor in mice treated with anti-tau antibodies, despite persistent brain hypoperfusion and neurovascular dysfunction. These data therefore identify a causal link between dietary salt, blood vessel endothelial dysfunction, and tau pathology — independent of blood-circulatory insufficiency. Authors suggest that “avoidance of excessive salt intake and maintenance of vascular health may help delay vascular and neurodegenerative pathologies that underlie dementia in the elderly.” More studies on this phenomenon are warranted.
DwN
Nature 31 Oct 2019; 574: 686-690