Hypertension, dietary salt and cognitive impairment

Abstract

Dementia is growing at an alarming rate worldwide. Although Alzheimer disease is the leading cause, over 50% of individuals diagnosed with Alzheimer disease have vascular lesions at autopsy. There has been an increasing appreciation of the pathogenic role of vascular risk factors in cognitive impairment caused by neurodegeneration. Midlife hypertension is a leading risk factor for late-life dementia. Hypertension alters cerebrovascular structure, impairs the major factors regulating the cerebral microcirculation, and promotes Alzheimer pathology. Experimental studies have identified brain perivascular macrophages as the major free radical source mediating neurovascular dysfunction of hypertension. Recent evidence indicates that high dietary salt may also induce cognitive impairment. Contrary to previous belief, the effect is not necessarily associated with hypertension and is mediated by a deficit in endothelial nitric oxide. Collectively, the evidence suggests a remarkable cellular diversity of the impact of vascular risk factors on the cerebral vasculature and cognition. Whereas long-term longitudinal epidemiological studies are needed to resolve the temporal relationships between vascular risk factors and cognitive dysfunction, single-cell molecular studies of the vasculature in animal models will provide a fuller mechanistic understanding. This knowledge is critical for developing new preventive, diagnostic, and therapeutic approaches for these devastating diseases of the mind.

Keywords: Alzheimer disease; cerebrovascular disease; dementia; endothelial dysfunction; neurovascular coupling.

Figure 1.

Over 50% of cases of clinically diagnosed Alzheimer disease (AD) feature vascular pathology. AD represents 70% of cases of late-life dementia, diagnosed according to clinical criteria. However, post-mortem neuropathological analysis reveals that only 24% of dementia cases feature exclusively AD pathology (amyloid plaques and neurofibrillary tangles), while over 50% feature vascular pathology, either alone (26%) or mixed with AD pathology (27%).

Figure 2.

Mechanisms of slow-pressor Ang II HTN-induced neurovascular dysfunction. Circulating Ang II activates ROS production in the subfornical organ (SFO) leading to increased vasopressin (AVP) release from the hypothalamic paraventricular nucleus. AVP, in turn, leads to upregulation of endothelin-1 (ET1) in cerebral arterioles. ET1 and Ang II contribute to vascular oxidative stress and neurovascular dysfunction through ET_A and AT1 receptors, respectively.

Figure 3.

PVM mediate cerebrovascular dysfunction in slow-pressor Ang II HTN but not acute Ang II HTN. In slow-pressor Ang II HTN and BPH mice (left), circulating Ang II crosses the BBB and acts on AT1R on PVM to increase production of ROS by activating a Nox2-containing NADPH oxidase. Nox2-derived radicals, in turn, cause neurovascular dysfunction and cognitive deficits. ET1 also plays a role in the dysfunction (see Figure 2), but it remains unclear how this peptide contributes to ROS production in PVM. In contrast, in acute administration of pressor doses of Ang II (right), circulating Ang II activates AT1R and Nox2 on endothelial cells to increase ROS production and induce neurovascular dysfunction.

Figure 4.

Dietary salt induces endothelial dysfunction and cognitive deficits. High dietary salt stimulates Th17 polarization in the gut leading to increased circulating IL-17. IL-17 acts on the cerebral endothelium to induce inhibitory phosphorylation of eNOS through Rho-kinase, thus reducing NO production and bioavailability. The resulting endothelial dysfunction in the cerebral vasculature is associated with cognitive impairment. Remarkably, neurovascular coupling is not affected. Of note, PVM do not play a role in the cerebrovascular dysfunction of dietary salt.