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

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).

Alzheimer’s disease (AD), a devastating neurodegenerative disorder characterized by cognitive decline and memory loss, affects over 500 000 Canadians and is expected to double in incidence in the next 15 years*. A singular cause of AD is unlikely because its pathology is thought to be 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 to name a few. In addition, a reduction in plasmalogen levels, a class of phospholipids containing a vinyl-ether bond, in the circulation and brains of AD patients has been demonstrated. Research into the association between plasmalogen deficiency and cognition is growing, with emphasis on whether plasmalogen replacement might offer therapeutic benefits.

In this post, we highlight the findings of a study by Che et al, showing that treatment with eicosapentaenoic acid (EPA)-enriched ethanolamine plasmalogens (EPA-pPE) and EPA-enriched phosphatidylethanolamine (EPA-PE) was able to improve Aβ, p-tau, and oxidative stress. Researchers chose to include EPA (omego-3 fatty acid) as the sn-2 constituent because it is believed to support brain function and be beneficial for neurological disorders. 

Rats received either a lateral ventricle injection of aggregated Aβ42 to induce AD, or a saline solution for the sham group. Compared to the sham group, the rats injected with Aβ42 showed an increase in Aβ accumulation in the hippocampus and p-tau levels. Both EPA-pPE and EPA-PE were equally effective in reducing amyloid accumulation by ~60%. However, EPA-pPE showed enhanced results compared to the EPA-PE treatment in reducing the ratio of p-tau to tau, with EPA-pPE lowering p-tau/tau levels by 60% and EPA-PE only reducing by 30%.

Oxidative stress is caused when free radicals damage lipids in the cellular membrane and largely contributes to the neuronal damage in AD. To determine whether either treatment influenced oxidative stress, the antioxidant enzyme superoxide dismutase (SOD) and a product of lipid peroxidation, malondialdehyde (MDA), were measured within cortical tissue. Aβ42-injected rats displayed a decrease in SOD and an increase in MDA compared with sham animals, indicating more oxidative stress. EPA-PE did not increase SOD activity and only marginally reduced MDA concentrations (from 19 noml/g to 16 noml/g). However, treatment with EPA-pPE was able to increase SOD activity by ~25% and reduce MDA concentration from 19 noml/g to 11 noml/g, indicating that these rats had more protection against oxidative stress compared to the untreated rats. Plasmalogens are known antioxidants and thus treatment with EPA-pPE resulted in lipid incorporation into the cell membrane, preventing further lipid peroxidation and free radicals from forming.

Together, Che et al have demonstrated the importance of plasmalogens in many of the characteristic pathologies of AD. It is interesting to note that although both treatments were effective in improving many AD pathologies to some degree, the treatment containing plasmalogens was overall far more successful in this model. The main difference between the two treatments is the presence of the vinyl-ether bond at sn-1 in plasmalogens, while the phosphatidylethanolamine has an acyl bond at this position. This finding highlights the importance of the vinyl-ether bond, which is responsible for the antioxidant and structural roles of this class of lipids. Presence of toxic proteins and oxidative stress can lead to extensive neuronal damage and further downstream effects to remove the injured cells, but these studies support that increasing plasmalogens may be protective. One important critique of this work is that lipids levels were not investigated before or after the lipid treatment, so it cannot be stated whether either EPA-pPE or EPA-PE were able to alter plasmalogen levels in the rats. In further work, Che et al examine the mechanisms behind the AD-associated reduced neuronal density including those involved in loss of neuronal plasticity and apoptosis and whether EPA-pPE or EPA-PE can effectively rescue these other AD pathologies.

*Alzheimer’s Society of Canada. (2016) Dementia numbers in Canada. https://alzheimer.ca/en/Home/About-dementia/What-is-dementia/Dementia-numbers