Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice

A representation of a microglial cell and amyloid plaques within a network of neurons.

Ifuku M, Katafuchi T, Mawatari S, Noda M, Miake K, Sugiyama M, and Fujino T. (2012) Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice. Journal of Neuroinflammation 9(197)

Plasmalogens are a class of lipids that contain a vinyl-bond at sn-1, causing these lipids to have unique characteristics. The double bond gives plasmalogens a more compact structure providing membranes with more organization and less fluidity, a characteristic that is essential for vesicular fusion. Plasmalogens have also been shown to be excellent scavengers of radial oxygen species giving these lipids antioxidant properties. Due to the variety of roles that plasmalogens have in cells, it is unsurprising that reduced levels of plasmalogens in the cortex and hippocampus are associated with the development of Alzheimer’s disease (AD). AD is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Many factors are thought to be involved in the risk for AD including accumulation of toxic proteins, impaired cholesterol transport, poor diet, mental illness, and a reduction in plasmalogen level. Lipopolysaccharide (LPS; more information about LPS can be found here) administration is used as a model for neurodegeneration because it causes impairment of cognitive behavior, suppresses neurogenesis, and leads to neurodegeneration. To determine if plasmalogen supplementation could improve AD pathology, Ifuku et al treated LPS-induced AD mice with plasmalogens extracted from chicken breast at a dose of 20mg/kg through intraperitoneal (i.p.) injection and determined the impact on weight, microglial activation, cytokine expression, Aβ accumulation, and plasmalogen levels.

After a week of LPS administration, the treatment caused weight loss and showed a significant difference on days 4-8 (~28g) compared to the control group (~34g). However, in the animals treated with both LPS and plasmalogens, the weights were not found to be different from either the control group or the group who were treated with only plasmalogens without having received LPS. Their weight showed a drop to ~31g on days 4 and 5 but increased to ~33g by day 8. The fact that the plasmalogen treatment was able to recover the weight loss indicates that it may provide some protection from the effects of LPS.

To analyze the inflammatory response to LPS and whether plasmalogen treatment had any benefit, immunohistochemistry and immunofluorescence were used. A microglia marker, Iba-1, and an astrocyte marker, GFAP, were visualized in the prefrontal cortex (PFC) and CA1 of the hippocampus in the mice. In the animals that received LPS, there were significantly increased numbers of Iba-1-positive cells and GFAP-positive astrocytes compared to the control group, indicating that there was microglial activation and astrocytosis, signifying an neuroinflammatory response to LPS. Treatment with plasmalogens was able to return these levels to what was seen in the PFC and hippocampus in the control mice and mice that received only plasmalogens. In addition, the mRNAs of inflammatory cytokines, IL-1β and TNF-α, were both increased in the LPS treated mice compared to the control mice, but when also supplemented with plasmalogens, no difference was seen compared to the control group or the group that received only plasmalogens.

Finally, the LPS-treated mice had an increase in Aβ production compared to the control mice, but this was attenuated in the mice also treated with plasmalogens. When confirming the plasmalogen levels in the mice, the group that was treated with LPS showed a decrease in plasmalogens, however mice also treated with plasmalogens had levels similar to those seen in the control group.

Ifuku et al have demonstrated that plasmalogen treatment can attenuate the deficits caused by LPS administration including microglial activation, cytokine expression, Aβ production, and plasmalogen reduction. How the plasmalogens specifically aid in these symptoms is not known, but it can be theorized that the antioxidative effects of the lipids may recover any oxidative stress caused by the LPS. As well, plasmalogens are known to have a role in preventing the production of Aβ. This work also supports the use of LPS as a model of the clinical AD phenotype. Although the route of administration is not translatable to humans, Ifuku et al have shown that a treatment that could augment plasmalogen levels could prove effective in treating AD and would be worth investigating further.