Plasmalogens, the vinyl ether-linked glycerophospholipids, enhance learning and memory by regulating brain-derived neurotrophic factor.

Image of a whole mouse brain.

Hossain MS, Mawatari S, and Fujino T. (2022) Plasmalogens, the vinyl ether-linked glycerophospholipids, enhance learning and memory by regulating brain-derived neurotrophic factor. Frontiers in Cell and Developmental Biology

Plasmalogens are a class of phospholipids that contain a vinyl-ether bond at the sn-1 position. This double bond gives plasmalogens unique characteristics including antioxidative properties and roles in membrane structure and fluidity. Reduced plasmalogen levels are implicated in Alzheimer’s disease, a neurodegenerative disorder characterized by memory loss and cognitive decline, and are thought to play a role in its pathology. Interestingly, this association also implicates the role of plasmalogens in hippocampal-dependent memory. A known regulator of memory-related changes in the brain is brain-derived neurotrophic factor (BDNF). BDNF accomplishes this through influencing adult neurogenesis, synaptic protein expression, dendritic spine maturation, and synaptic plasticity. In addition, BDNF can recruit TrkB, one of its target receptors, to lipid rafts to induce cellular signaling. Hossain et al were interested in the role of plasmalogens in memory and whether it has a role in regulating BDNF-TrkB signaling. The authors also wanted to determine whether a plasmalogen treatment could improve memory in a plasmalogen-deficient mouse model.

Plasmalogen-deficient mouse models exist but result in a severe phenotype with high lethality and cataracts, therefore they do not make a great model for evaluating memory. To overcome this hurdle, Hossain et al developed a deficient model using lentivirus sh-RNA to knockdown glyceronephosphate O-acyltransferase (GNPAT), the first enzyme in the plasmalogen biosynthetic pathway, in the hippocampus. The Morris water maze was used to determine if memory was impaired following bilateral lentiviral injection. At both timepoints (1 week and 3 weeks after the injection) the group that received the sh-GNPAT injection demonstrated significantly increased escape latency compared to the group who received the control injection, indicating that learning performance was hindered by the plasmalogen reduction. When evaluating memory performance, there was a significant memory reduction in the group that was injected with sh-GNPAT compared to the control group, indicating that the plasmalogen reduction also affected spatial learning and memory in the mice. Plasmalogen levels were confirmed to be reduced in the hippocampus of sh-GNPAT mice after the animals were euthanized using liquid chromatography-mass spectrometry (LC-MS).

To determine if any memory-related gene expression was altered in the sh-GNPAT injected mice, GNPAT and Bdnf mRNA expression were measured. GNPAT mRNA levels were reduced both 1 and 3 weeks after injection of sh-GNPAT. Interestingly, Bdnf mRNA expression also demonstrated a significant reduction following sh-GNPAT injection.

After demonstrating that a plasmalogen reduction results in memory loss and decreased memory-related gene expression, Hossain et al tested whether a diet containing 0.01% plasmalogens could improve learning in mice. After 6 weeks, there was a significant increase in plasmalogen level in the hippocampus of mice fed the plasmalogen diet compared to the group that received the control diet. As well, the plasmalogen diet improved learning using the Morris water maze test and this improvement was not found to be caused by an improvement in physical activity since their swimming speed was not different between either diet group. Similar to the knockdown data above, the plasmalogen diet was found to enhance Bdnf, synapsin-1, PSD-95, and synaptotagmin-1 mRNA expression in the hippocampus. When the hippocampal lipid rafts of the sh-GNPAT injected mice were analyzed, they had reduced TrkB protein levels, but when the expression of TrkB in lipid rafts was analyzed in the hippocampus, mice fed with plasmalogen diet had increased levels of TrkB protein compared to the control fed group. To determine if the learning and memory improvement in the plasmalogen-fed group was dependent on BDNF-TrkB signaling, mice were injected with sh-RNA vectors against either TrkB or Bdnf 4 weeks after beginning to feed the mice the plasmalogen-diet, then the diet continued for another 2 weeks. In the Morris water maze, the improvement that had been seen in the plasmalogen fed group was attenuated in the sh-Bdnf or sh-TrkB injected mice. As well, the enhanced expression of Bdnf and TrkB was suppressed in the sh-Bdnf or sh-TrkB injected mice.

Hossain et al were interested in determining if plasmalogens have a role in memory and learning and if it can regulate BDNF-TrkB signaling. In mice where GNPAT was knocked down in the hippocampus, they demonstrated a reduction in plasmalogens, a decrease in memory and learning, and a reduction in BDNF and TrkB protein levels. Contrastingly, when mice were fed a diet with plasmalogens added, they showed enhanced plasmalogen levels, memory and learning, and BDNF and TrkB protein. Although the plasmalogen supplementation dose, at 0.01% of their diet, is very low, these findings suggest that plasmalogens do have a role in memory and learning and that this association is dependent on BDNF-TrkB signaling. It is also important to note that only the hippocampus is altered in these animals but in neurodegenerative diseases many brain regions and other organs would be affected. Further work looking at a higher plasmalogen supplementation dose could confirm these findings and possibly demonstrate further improvements. It would also be interesting to examine whether a plasmalogen treatment could alleviate all effects of GNPAT knockdown.