Plasmalogen attenuates the development of hepatic steatosis and cognitive deficit through mechanism involving p75NTR inhibition.

The fat accumulation in a liver with hepatic steatosis.

Liu Y, Cong P, Zhang T, Wang R, Wang X, Liu J, Wang X, Xu J, Wang Y, Wang J, and Xue C. (2021) Plasmalogen attenuates the development of hepatic steatosis and cognitive deficit through mechanism involving p75NTR inhibition. Redox Biology, 43

Plasmalogens are a class of lipids that contain a vinyl-ether bond at the sn-1 position on a glycerol backbone. This double bond gives plasmalogens a compact structure which influences membrane organization and vesicular fusion. As well, it provides antioxidant properties through the ability of the double bond to scavenge two radical oxygen species. Plasmalogen levels are known to decrease in metabolic diseases including obesity, liver disease, and Alzheimer’s disease (AD). AD is a devastating neurodegenerative disorder characterized by cognitive decline and memory loss. A single cause of AD is unlikely as its pathology is associated with many risk factors including the accumulation of toxic proteins such as beta-amyloid (Aβ) and hyperphosphorylated tau (p-tau), impaired cholesterol transport, poor diet, heart disease, high alcohol consumption, mental illness, and lack of physical activity. Plasmalogen levels have also been shown to decrease in the brains of people with AD. Liu et al were interested in the relationship between p75 neurotrophin receptor (p75NTR), a receptor that has a critical role in production of Aβ, neuronal death, neurite degeneration, and p-tau, all of which are involved in the pathology of AD, and plasmalogens and how they alter steatohepatitis (fatty liver disease characterized by inflammation of the liver and fat accumulation) and memory impairments.

To determine the role of plasmalogens in steatohepatitis, two mouse models were used. The first was the amyloid precursor protein (APP) and presenilin-1 (PS1) double knockout mutant mice to model AD, and the second an obesity model, produced by feeding mice a high fat high sucrose diet (HFSD) for 12 weeks. The mice were supplemented with 0.1% plasmalogens extracted from Calceolaria frondosa, a type of sea cucumber, in their diet for 16 weeks to determine if recovering plasmalogen levels could also recover steatosis in either model. The APP/PS1 mice were confirmed to have a decrease in plasmalogens in the hippocampus compared to the wild-type mice. In addition, the genes that encode enzymes required for plasmalogen synthesis (Gnpat and Apgs) had reduced mRNA levels in the hippocampus and liver of APP/PS1 mice. The hippocampus also had decreased mRNA levels of peroxisome homeostasis genes (Pmp70, Pex14, and Pex16), suggesting that there is peroxisomal dysfunction in AD. These results were also found in the HFSD-fed group, indicating that the high fat diet caused a reduction in plasmalogens and reduced Gnpat expression.

Expression of p75NTR was measured in liver and hippocampus of HFSD-fed mice and found to be upregulated. This effect was also seen in the APP/PS1 mice. One interesting overlap between the two mouse models used in this study is that the APP/PS1 mice have steatosis and lipid accumulation in the brain. Because of this, Liu et al wanted to determine how plasmalogen supplementation would affect the steatosis in APP/PS1 and HFSD-fed animals. The plasmalogen treated animals showed reduced lipid accumulation in the hippocampus and liver in the APP/PS1 mice, as well as decreased hepatic triglyceride levels. Plasmalogen treated HSFD-fed mice also showed reduced hepatic lipid accumulation shown through triglyceride levels and liver histology. In determining the mechanism behind these changes, it was also found that plasmalogen treatment reduced protein levels of p75NTR, increased ATGL, and increased phosphorylation of HSL, which would indicate that plasmalogen treatment inhibits p75NTR and induces lipolysis, causing the reduction in lipid accumulation.

To investigate if plasmalogens could improve cognitive impairment in APP/PS1 mice, after 16 weeks of plasmalogen supplementation the Morris water maze and radial 8-arm test were used to study spatial learning and working memory performance. Compared to wild-type mice, APP/PS1 animals showed an increased escape latency and impaired learning ability. By the 5th day of training wild-type animals spent most of their time in the target quadrant (~37% in target and under 25% in each of the other three) while the APP/PS1 mice swam randomly in each quadrant (~25% in target and 20-30% in the other three). With plasmalogen treatment, there was an increase in the percentage of time that APP/PS1 mice spent in the target quadrant and matching that seen by the wild-type animals at ~37% of time spent in the target and under 25% in the other three quadrants. In addition, wildtype animals and the APP/PS1 mice treated with plasmalogens were found to use a spatial strategy while the APP/PS1 animals used a repeated loop strategy.

The relationship between a reduced plasmalogen level and AD and other metabolic diseases has been established. Lie et al demonstrated that there is a link between p75NTR, plasmalogens, and their role in fatty liver disease. They showed that a similar reduction in plasmalogens is seen between both the APP/PS1 model and the HFSD-fed animals, and interestingly, both were found to have plasmalogen reductions in the brain and liver. One of the locations that plasmalogens are largely synthesized is in the liver, therefore it is unsurprising to observe a reduction in liver disease, however seeing a similar reduction in an AD model is interesting. One theory that describes the reduction of plasmalogens in AD is that plasmalogen biosynthesis primarily occurs in the liver and plasmalogens are transported to the brain, which could also explain the association between liver disease and AD. As well, Liu et al demonstrated that the APP/PS1 mice are cognitively impaired compared to the wild-type animals as they have impaired spatial memory and working memory, however plasmalogen supplementation was able to recover their learning ability. This work provides support for long-term plasmalogen treatments being a potential therapy for those with AD in helping improve or sustain cognition, as well as balancing p75NTR expression in the brain, resulting in protection against neurodegeneration.