Plasmalogen improves memory function by regulating neurogenesis in a mouse model of Alzheimer’s diseases.

Li R, Xiong W, Li B, Li Y, Fang B, Wang X, and Ren F. (2023) Plasmalogen improves memory function by regulating neurogenesis in a mouse model of Alzheimer’s diseases. International Journal of Molecular Sciences

Plasmalogens are a unique class of phospholipid that contain a vinyl-ether bond at the sn-1 position of the glycerol backbone. This bond causes plasmalogens to have a more compact structure making this class of lipid important in membrane structure and fluidity, cholesterol transport, lipid raft formation, and vesicular fusion. Interestingly, reduced levels of plasmalogens have been associated with Alzheimer’s disease (AD) which suggests that it may have a causative role in the disease. AD is characterized by memory loss and cognitive decline which can make caring for oneself difficult. In the brain the hippocampus, responsible for learning and memory, is one of the first regions that shows damage in the progression of AD. There is an essential process called adult hippocampal neurogenesis (AHN) that occurs where neural stem cells undergo proliferation and differentiation resulting in new neurons. Altered AHN earlier in adulthood is associated with neuronal vulnerability in AD however, improving this process has been demonstrated to recover AD pathology and improve cognitive function in people with AD. Since plasmalogens have important roles in membrane structure and in neuronal functions, Li et al wanted to determine if plasmalogen supplementation altered neural stem cell proliferation in cells also treated with beta-amyloid (Aβ) 1-42, a toxic protein associated with AD, or the AHN process in a mouse model of AD.

To mimic the viability of neural stem cells that would be present in a brain with AD, C17.2 cells were treated with 5 µM of Aβ (1-42) and were found to be 63.3% as viable as the control cells. Next, they tested if pre-treating with a plasmalogen supplement, extracted from scallops, at either 1 µg/mL, 5 µg/mL, 10 µg/mL, or 20 µg/mL for two hours could mitigate the effects of 24 hours of exposure to Aβ (1-42) exposure. Compared to the cells that were not supplemented with plasmalogens, those that received 5 µg/mL or higher showed significantly improved vitality. To determine how Aβ (1-42) and plasmalogen supplementation affect differentiation of neural stem cells, they were administered 5 µM of Aβ (1-42) or 5 µM of Aβ (1-42) and 10 µg/mL plasmalogens for seven days. After this, Nestin mRNA, a neural stem cell marker, and MAP2 mRNA, a mature neuronal marker, were quantified. A downregulation of MAP2 and an upregulation of Nestin in the Aβ (1-42) treated cells was seen compared to the control cells. In contrast, supplementation of plasmalogens caused a reversal of these effects.

The mouse model of AD used were APP/PS1 transgenic mice which express the mouse/human amyloid precursor protein (APP) and mutated human presenilin 1 (PS1). Presenilin-1 is one of the core proteins in the gamma secretase complex and is involved in cleaving APP, producing Aβ (1-42). Together, these mutations result in a high production of Aβ (1-42) which can accumulate in neurons and cause degeneration. The APP/PS1 transgenic female mice were sixteen weeks old and were separated into three groups consisting of 12 animals: the control group with wild-type mice, the AD group with APP/PS1 mice, and the AD-plasmalogen group with APP/PS1 mice that were supplemented with 67 mg/kg/day of plasmalogens by oral gavage for six weeks. To determine the difference in neurogenesis between wild-types and the transgenic model, the number of new neurons labelled with the DCX antibody, used to detect neurogenesis, were quantified. An 81% decrease in DCX-expressing cells was seen in the hippocampus of the AD mouse group compared to the control group. The AD mice that also received plasmalogen supplementation showed a significant increase in DCX-expressing cells compared to the AD mice and nearly recovering the levels seen in the control mice. To demonstrate whether this improvement translated to improved memory function, the novel object recognition (NOR) was employed. The control group spent more time with the novel objects while the AD group had a decreased discrimination index ratio. However, the plasmalogen supplemented AD group showed a preference for the novel objects, suggesting that the supplementation prevented some of the memory loss in these animals. 

Li et al were interested in elucidating the role of plasmalogens in AHN and determine if supplementing with plasmalogens can protect against the progression and pathology of AD. They demonstrated that an AD model of cell culture has a decreased viability however plasmalogen supplementation significantly improved this. Also, plasmalogen supplementation in an AD mouse model was found to nearly recover the DCX-expressing levels as that seen in the controls compared to the 81% decrease seen in the AD mice. As well, the plasmalogens caused the AD group to spend more time with novel objects, increasing their discrimination index ratio. Here, Li et al have demonstrated that plasmalogen supplementation can help prevent some of AD progression through allowing the proliferation and differentiation of neural stem cells and by minimizing memory deterioration. This work provides support for the use of plasmalogens in a potential AD treatment, especially as a preventative measure.