Vascular nitric oxide, sex hormone replacement, and fish oil may help to prevent Alzheimer's disease by suppressing synthesis of acute-phase cytokines

Abstract

The neurodegenerative plaques of Alzheimer's disease (AD) are characterized by a self-sustaining acute-phase reaction in which both interleukin-1 (IL-1) and interleukin-6 (IL-6) are up-regulated. The fact that IL-6 is detectable in early stage diffuse plaques encourages the speculation that the acute-phase process is crucial to the pathogenesis of AD. The epidemiological association of AD with estrogen deficiency, as well as with various disorders characterized by vascular endotheliopathy, suggest a protective role for vascular nitric oxide (NO). NO has an autocrine anti-inflammatory impact on endothelium, owing in part to antagonism of NF-κB activity; since induction of IL-6 is dependent on NF-κB, this may explain recent evidence that NOinhibits macrophage IL-6 production. It is reasonable to postulate that, analogously, cerebrovascular NOdecreases IL-6 production in the brain. Vascular NO may also have direct neuroprotective activity. Estrogen, in addition to promoting vascular NO synthesis, can block IL-6 production by a more direct mechanism in cells expressing estrogen receptors; since such receptors have been reported in brain glia and astrocytes, estrogen has the potential to limit brain IL-1 activity. Testosterone likewise can inhibit IL-6 induction in androgen-responsive cells, which may include brain glia and astrocytes. Since fish oil and γ linolenic acid (GLA) suppress IL-1 production by stimulated monocytes, they conceivably could exert this effect in the brain as well; the comparatively low prevalence of AD in elderly Japanese is intriguing in this regard. These considerations suggest that a healthy cerebrovascular endothelium, sex hormone activity, and dietary fish oil/GLA may slow or prevent AD onset by dampening acute-phase mechanisms in the brain.