Plasmalogens eliminate aging-associated synaptic defects and microglia-mediated neuroinflammation in mice.

Image of ascidians, commonly called sea squirts.

Gu J, Chem L, Sun R, Wang J, Wang J, Lin Y, Lei S, Zhang Y, Lv D, Jiang F, Deng Y, Collman JP, and Fu L. (2022) Plasmalogens eliminate aging-associated synaptic defects and microglia-mediated neuroinflammation in mice. Frontiers in Molecular Biosciences

Plasmalogens are a unique class of lipids that contain a vinyl-ether bond at sn-1 and constitute approximately 20% of all phospholipids in human tissues. In certain tissues like the brain, ethanolamine plasmalogens make up 60-80% of total ethanolamine phospholipids. Plasmalogens are essential for membrane dynamics, trafficking, vesicular fusion, and synaptic function. A reduction in plasmalogen levels has been associated with aging and neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Zellweger syndrome. Gu et al were interested in determining whether plasmalogen supplementation from ascidian tissue could prevent age-associated cognitive decline in aged, healthy mice using the Morris water maze (MWM), transmission electron microscopy (TEM), immunoblotting, and immunofluorescence.

Female C57BL/6J mice were used in this study at 16 months of age and were fed an ascidian-derived plasmalogen supplement (Pls-fed) for 2 months in water using intragastric administration at 300mg/kg once a day, 5 days a week. They were compared against 15 4-week-old mice used as a young control group. After the two months of treatment, MWM was performed to test cognition. The aged mice swam a longer distance and took more time to find the escape platform compared to the young mice, suggesting that cognitive impairments may have occurred in the aged animals. The aged Pls-fed group demonstrated a significantly shorter swimming distance and shorter escape latency on the 4th and 5th day of testing at ~3.5 meters and ~25 seconds, respectively, compared to the aged group at ~5 meters and ~40 seconds, respectively. To study spatial reference memory in the animals, the platform was removed and the aged Pls-fed mice spent significantly more time in the target quadrant (~20 seconds) compared to the aged mice (~15 seconds). These findings indicate that the plasmalogen supplementation provided a benefit for the aged animals in preventing some of the impairments in spatial learning and memory seen in the untreated aged animals.

To determine whether alterations in plasmalogen levels influenced synapse structure in the hippocampus, chosen because it is an area of the brain responsible for memory, TEM was utilized. A synapse is a specialized junction between neurons and is the location where a pre-synaptic neuron will release neurotransmitters to bind on the receptors of a post-synaptic neuron, allowing intercellular signaling. Many synaptic structures were found in both the young control mice and the aged Pls-fed mice and there were many more synapses seen in these animals compared to the aged, untreated animals. The young animals and the Pls-fed aged animals also have more synaptic vesicles, compartments made up of a single phospholipid layer that contain and transport neurotransmitters, compared to aged animals. Visually, dramatic deterioration of synapses and few vesicles was present in the aged animals, while Pls-fed aged animals showed intact synapses and many vesicles. These indicate that the plasmalogen supplementation protected the hippocampus from synaptic deterioration, suggesting that neuronal signaling would be more successful in the Pls-fed group.

Since learning and memory are associated with synaptic growth and remodeling, hippocampal synaptogenesis (the formation of synapses in the hippocampus) was also studied by Gu et al using immunoblotting and immunofluorescence. Immunofluorescence revealed that synaptophysin, an integral protein in synaptic vesicles, expression was reduced in the CA1 and DG areas of the hippocampus of aged mice. However, not only did the Pls-fed aged mice have significantly higher synaptophysin expression, synaptophysin was upregulated in the hippocampus of these animals. Together these results suggest that although synaptic plasticity decreases with age, plasmalogen supplementation is able to alleviate this effect.

Gu et al investigated whether plasmalogen supplementation could inhibit cognitive deficits caused by aging. They found that a plasmalogen supplement derived from ascidian tissue was able to prevent some of the cognitive decline found in the aged mice. This was determined through behavioural assays where aged animals required more time and took a longer route to find a target platform compared to young controls indicating cognitive decline, while Pls-fed aged animals behaved similarly to the young animals. As well, the plasmalogen supplementation was thought to inhibit synaptic deterioration seen morphologically and through analyzing synaptophysin expression. Keeping synpases intact allows neurons to continue to signal using vesicles, which were also found in higher amounts in Pls-fed animals. Plasmalogens are an important component of membranes and provide structure, influence organization, and aid in vesicular fusion. The findings above indicate that plasmalogen supplementation could prevent neurodegeneration and synaptic deterioration seen in aging. Gu et al suggest that administering plasmalogens could be an option to reduce cognitive decline and maintain cognitive function as people age.