EPA-enriched ethanolamine plasmalogen and EPA-enriched phospatidylethanolamine enhance BDNF/TrkB/CREB signaling and inhibit neuronal apoptosis in vitro and in vivo

Che H, Zhang L, Ding L, Xie W, Jiang X, Xue C, Zhang T, and Wang Y. (2020). EPA-enriched ethanolamine plasmalogen and EPA-enriched phospatidylethanolamine enhance BDNF/TrkB/CREB signaling and inhibit neuronal apoptosis in vitro and in vivo. Food Funct., 22(1729).

Alzheimer’s disease (AD) is a very common neurodegenerative disorder with the primary clinical manifestations being cognitive decline and memory loss. There is not a known cause for AD, but it appears to result from the additive effect of many risk factors. One consistent finding in post-mortem AD brain samples is volume loss in the cortex and hippocampus. A significant factor in this neuronal loss is a dysfunction of apoptosis, the process of organized cell death. In a healthy brain, apoptosis allows for proper pruning of excess or injured neurons, especially in a developing brain, but is also thought to have a role in neurodegenerative disorders when the underlying mechanisms are dysregulated. In addition, neuronal plasticity is an important characteristic of a healthy brain, as neurons must be able to alter their function in response to changes in their environment.

In a previous article from 2018 (1), Che et al found that two families of proteins involved in apoptosis, B-cell lymphoma 2 (Bcl-2) and caspases, were increased in the Aβ42-induced AD rat model, but decreased after treatment with either eicosapentaenoic acid (EPA)-enriched ethanolamine plasmalogens (EPA-pPE) or EPA-enriched phosphatidylethanolamine (EPA-PE), however there was no consistency in whether one was more effective than the other mechanistically. This finding would suggest that perhaps alternate pathways, not analyzed in the initial study, may underlie their role in regulating apoptosis. Presently, they have advanced this work by investigating the role that these treatments have on neuronal loss and plasticity by analyzing neurotrophins, levels of apoptosis, and dendrite length and density in both a primary hippocampal neuronal cell culture and an Aβ42-induced AD rat model.

Neurotrophins are known to be reduced in AD patients, with three of the most important neurotrophins for neuronal plasticity being brain-derived neurotrophic factor (BDNF), post-synaptic density protein 95 (PSD 95), and synaptophysin (SYN). All three were analyzed using Western blots and were reduced in the Aβ42-injected rats compared to the sham group. EPA-pPE and EPA-PE were both able to produce almost 4-fold greater levels of BDNF, far surpassing that seen in the sham rat group. In addition, while SYN and PSD 95 were also improved by both treatments, EPA-pPE showed greater improvement with a 100% greater increase for both SYN and PSD 95 compared to EPA-PE, which improved SYN by 25% and PSD 95 by 40%. An increase in these neurotrophins would indicate that the lipid treatments successfully improved neuronal plasticity in the AD-induced rats.

As well as neurotrophins, neuronal volume is reduced in AD patients, therefore neuronal density in the cortex and hippocampus were examined using Nissl staining, while silver staining showed the axons and dendrites of the neurons. Sham animals had evenly stained and regularly shaped neurons, but the Aβ42-injected rats had a reduced density of neurons, similar to those observed typically in AD patients. Both EPA-pPE and EPA-PE appeared to reverse this damage, however EPA-pPE showed greater success than EPA-PE. The Aβ42-injected rats also had a reduction in the number and length of axons compared to the rats in the sham group. Both EPA-pPE and EPA-PE treatments resulted in increased neuronal branching and axonal length, however EPA-pPE again resulted in a more pronounced benefit in the AD-induced group.

These findings lend support for the use of plasmalogens to improve apoptosis and neuronal plasticity in AD patients and their potential role in benefiting cognition. As seen in their earlier work and discussed further in a prior blog post, EPA-pPE was again found to be more effective than EPA-PE. Although both were effective at rescuing the effects of Aβ42, EPA-pPE showed far greater improved neurotrophin levels of SYN and PSD 95, but also had improved neuronal density, neuronal branching, and axonal length compared to the EPA-PE treatment. Given that neuronal plasticity is central to cognitive deficits and memory loss, these findings are highly relevant for AD. The main difference between these treatments is the vinyl-ether bond at sn-1 in the plasmalogen of EPA-pPE, and here we see further evidence that this treatment in particular was more protective against Aβ42-induced AD pathologies than EPA-PE. As this treatment also appears to be multi-targeting, plasmalogens may be a potential long-term therapy for AD patients to help improve the underlying mechanisms of cognitive decline and memory loss.

1)Che H, Le Q, Zhang T, Ding L, Zhang L, Shi H, Yanagita T, Xue C, Chang Y, and Wang Y. (2018) A comparative study of EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine on Aβ42 induced cognitive deficiency in a rat model of Alzheimer’s disease. Food Funct., 9 (3008).