Plasmalogens Eliminate Aging-Associated Synaptic Defects and Microglia-Mediated Neuroinflammation in Mice

Abstract

Neurodegeneration is a pathological condition in which nervous system or neuron losses its structure, function, or both leading to progressive neural degeneration. Growing evidence strongly suggests that reduction of plasmalogens (Pls), one of the key brain lipids, might be associated with multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Plasmalogens are abundant members of ether-phospholipids. Approximately 1 in 5 phospholipids are plasmalogens in human tissue where they are particularly enriched in brain, heart and immune cells. In this study, we employed a scheme of 2-months Pls intragastric administration to aged female C57BL/6J mice, starting at the age of 16 months old. Noticeably, the aged Pls-fed mice exhibited a better cognitive performance, thicker and glossier body hair in appearance than that of aged control mice. The transmission electron microscopic (TEM) data showed that 2-months Pls supplementations surprisingly alleviate age-associated hippocampal synaptic loss and also promote synaptogenesis and synaptic vesicles formation in aged murine brain. Further RNA-sequencing, immunoblotting and immunofluorescence analyses confirmed that plasmalogens remarkably enhanced both the synaptic plasticity and neurogenesis in aged murine hippocampus. In addition, we have demonstrated that Pls treatment inhibited the age-related microglia activation and attenuated the neuroinflammation in the murine brain. These findings suggest for the first time that Pls administration might be a potential intervention strategy for halting neurodegeneration and promoting neuroregeneration.

Plasmalogens and platelet‐activating factor roles in chronic inflammatory diseases

“…111 Previously, orally supplementing mice with an alkylglycerol mix also successfully rescued adipocyte morphology changes, while reducing diet-induced obesity. 112 During aging, a recent study by Gu et al (2022) indicates that systemically administering Pls to female mice for 2 months starting at 16 months of age increases hippocampal synaptic density and plasticity, as well as neurogenesis and cognitive performance, while decreasing hippocampal microglial reactivity (on a morphological level) and the concentration of inflammatory mediators (tumor necrosis factor α, interleukins 1β and 6). 109 In this study, purified Pls derived from the ascidian Halocynthia roretzi enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with other omega-3 fatty acids, were used.…”

“…112 During aging, a recent study by Gu et al (2022) indicates that systemically administering Pls to female mice for 2 months starting at 16 months of age increases hippocampal synaptic density and plasticity, as well as neurogenesis and cognitive performance, while decreasing hippocampal microglial reactivity (on a morphological level) and the concentration of inflammatory mediators (tumor necrosis factor α, interleukins 1β and 6). 109 In this study, purified Pls derived from the ascidian Halocynthia roretzi enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with other omega-3 fatty acids, were used. 109 Omega-3 fatty acids were importantly shown in a human clinical trial conducted in middle-age adults to slow down accelerated aging and reduce the depression risk by lowering overall inflammation and cortisol levels during stress, in addition to promoting immune repair mechanisms during recovery.…”

“…109 In this study, purified Pls derived from the ascidian Halocynthia roretzi enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), together with other omega-3 fatty acids, were used. 109 Omega-3 fatty acids were importantly shown in a human clinical trial conducted in middle-age adults to slow down accelerated aging and reduce the depression risk by lowering overall inflammation and cortisol levels during stress, in addition to promoting immune repair mechanisms during recovery. 113 There is also recent evidence that EPA and DHA supplements protect against inflammation via the production of lipoxygenase and P450 cytochrome, in correlation with less severe depressive symptoms and increased molecular mediators of hippocampal neurogenesis.…”

Orally Administered Plasmalogens Alleviate Negative Mood States and Enhance Mental Concentration: A Randomized, Double-Blind, Placebo-Controlled Trial

“…Moreover, a simple method was developed to extract a large number of plasmalogens from animals ( Mawatari et al, 2007 ; Mawatari et al, 2009 ), which enabled research on plasmalogen treatment. In mice, plasmalogen administration not only suppressed inflammation-induced activation of microglia, amyloid formation, and neuronal cell death in the brain but also improved cognitive function ( Ifuku et al, 2012 ; Katafuchi et al, 2012 ; Hossain et al, 2013 ; Hossain et al, 2018 ; Gu et al, 2022 ; Hossain et al, 2022 ). A randomized controlled trial demonstrated that scallop-derived purified plasmalogens improved cognitive function in patients with mild AD or mild cognitive impairment ( Fujino et al, 2017 ; Fujino et al, 2018 ).…”

Transient Ca2+ entry by plasmalogen-mediated activation of receptor potential cation channel promotes AMPK activity

“…Plasmalogens are also involved in the regulation of protein kinase B (AKT) in Schwan cells, mouse embryonic fibroblasts, and neurons (da Silva et al, 2014;Malheiro et al, 2019;da Silva et al, 2021). In addition, supplementation of plasmalogens activates signaling pathways mediated by AKT, ERK, and brain-derived neurotrophic factors in cultured cells (Hossain et al, 2016;Che et al, 2020) and mice (Hossain et al, 2022), giving rise to enhanced learning and memory (Gu et al, 2022;Hossain et al, 2022), suggesting a potential function of plasmalogens in the regulation of signaling pathways.…”