LXA4 Levels in the Brain Decrease With Age, Perhaps Increasing Inflammation and Accelerating Neurodegeneration
Chronic inflammation in brain tissue is connected to the onset and progression of neurodegenerative conditions, so it is reasonable to expect that researchers will, from time to time, discover evidence for regulators of inflammation to be involved in aging and neurodegeneration. Here, scientists discuss LXA4, which has a role in resolution of the inflammatory response, and declines in abundance with age. Delivery of LXA4 produces functional benefits and greater resistance to inflammation in mouse models, making it a potentially interesting target for the development of therapies. The question, as always for attempts to suppress age-related inflammation, is whether this will reduce pathological, excess inflammation only, leaving necessary inflammation untouched. The side-effects of reducing necessary inflammation include increased cancer risk and vulnerability to pathogens, particularly undesirable in later life.
Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators.
Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice.
We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associated with cognitive performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.