Plasmalogens and Alzheimer's disease: a review

Abstract

Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and were correlated with cognition deficit and severity of disease. Limited studies showed positive therapeutic outcomes with plasmalogens interventions in AD subjects and in rodents. The potential mechanisms underlying the beneficial effects of PlsEtns on AD may be related to the reduction of γ-secretase activity, an enzyme that catalyzes the synthesis of β-amyloid (Aβ), a hallmark of AD. Emerging in vitro evidence also showed that PlsEtns prevented neuronal cell death by enhancing phosphorylation of AKT and ERK signaling through the activation of orphan G-protein coupled receptor (GPCR) proteins. In addition, PlsEtns have been found to suppress the death of primary mouse hippocampal neuronal cells through the inhibition of caspase-9 and caspase-3 cleavages. Further in-depth investigations are required to determine the signature molecular species of PlsEtns associated with AD, hence their potential role as biomarkers. Clinical intervention with plasmalogens is still in its infancy but may have the potential to be explored for a novel therapeutic approach to correct AD pathology and neural function.

Keywords: Alzheimer’s disease; Biomarker; Mechanisms of action; Plasmalogens; Therapeutic efficacy.

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Figures

Fig. 1

Chemical structures of Plasmalogens. R1 = palmitic acid (16:0) or stearic acid (18:0) or oleic acid (18:1). R2 = arachidonic acid (20:4) or docosahexaenoic acid (22:6) or oleic acid (18:1) or linoleic acid (18:2). When there is no double bond in the alkyl chain in the 1-position, the plasmalogens are referred to as alkyl plasmalogens, in contrast to when there is a double bond, as shown here, and they are referred to as alkenyl plasmalogens

Fig. 2

Biosynthetic pathway of Plasmalogens. Abbreviations: DHAP, dihydroxyacetone phosphate; DHAPAT, dihydroxyacetone phosphate acyltransferase; DHAP, dihydroxyacetone phosphate; ADHAP-S, alkyl dihydroxyacetone phosphate synthase; FAR1/2, acyl-CoA reductase 1 and 2

Fig. 3

Proposed mechanistic association of ethanolamine plasmalogens deficiency and Alzheimer’s disease. Abbreviations: Aβ, β-amyloid; PlsEtns, ethanolamine plasmalogens; VLCFAs, very long chain fatty acids. PlsEtns have a close association with Alzheimer’s disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and are correlated with cognition deficit and severity of disease, although it is not known whether it is the cause or the consequence of the disease. It has been suggested maybe it is both. A few possible mechanisms with regards to the decrease of PlsEtns in AD have been suggested: peroxisome dysfunction, oxidative stress, alterations in membrane lipid rafts and inflammatory responses. Decreased PlsEtns may further enhance oxidative damage and alter membrane properties in AD. This plus increased membrane free cholesterol associated with PlsEtns deficiency could increase the production of Aβ. Aβ and reactive oxygen species could further decrease PlsEtns level. PlsEtns are major lipids facilitating membrane fusion of synaptic vesicles associated with neurotransmitter release, thus loss of PlsEtns could potentially contribute to the synaptic dysfunction and neurotransmitter depletion in Alzheimer’s disease. The association of decreased level of PlsEtns and neuroinflammation may be related to antioxidant properties of plasmalogens that protect cells from oxidative stress. Neuroinflammation has been reported to be associated with Aβ accumulation