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. 2022 Feb 23:9:815320.
doi: 10.3389/fmolb.2022.815320. eCollection 2022.

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

Jinxin Gu  1 , Lixue Chen  1 , Ran Sun  1 , Jie-Li Wang  2 , Juntao Wang  1 , Yingjun Lin  1 , Shuwen Lei  1 , Yang Zhang  1 , Dan Lv  1 , Faqin Jiang  1 , Yuru Deng  2 , James P Collman  3 , Lei Fu  1   4
Affiliations

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

Jinxin Gu et al. Front Mol Biosci. .

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.

Keywords: aging; microglia; neurogenesis; neuroinflammation; plasmalogen; synaptogenesis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The chemical structure of plasmalogens. Plasmalogen is characterized by a vinyl ether linkage with 16:0, 18:0, and 18:1 hydrocarbon chains at sn-1 position, an ester bond linking PUFAs at sn-2 position, and a phosphate group at sn-3 position (X denotes ethanolamine or choline) of the glycerol backbone.
FIGURE 2
FIGURE 2
Effects of 2-months Pls supplementation on the appearance and cognitive behaviors of aged mice. (A) Representative photos of young mice (3 months), aged Pls-fed mice (18 months), aged control mice (18 months). (B–E) Spatial reference learning and memory were determined and characterized in a Morris water maze study. Mice were trained in Morris water maze for consecutive 5 days, four trials per day. The probe trials were tested on the 6th day. The distance traveled (B) and time spent (C) to reach the escape platform are demonstrated respectively. A bar graph summarizes the time spent within the target quadrant (D) and platform crossing numbers (E). Data are presented as mean ± SEM, with 13–16 mice in each group (Young, n = 14; Aged control, n = 13; Aged Pls-fed, n = 16). Asterisks indicate statistical significances compared to Aged control using one-way ANOVA; Statistical significance (*p < 0.05; **p < 0.01).
FIGURE 3
FIGURE 3
TEM ultrastructural study on murine hippocampal CA1 region. The TEM micrographs of aged control mice (A), young control mice (B), and aged Pls-fed mice (C,D). Pre-synaptic terminals are marked with blue color, and post-synaptic domains with pink color. The synaptic loss, synaptic degradation and deterioration were observed in aged controls (A). On the contrary, abundant synaptic vesicles are present in the pre-synaptic terminals (marked in blue) of young controls (B). There is a pronounced increase in the numbers and density of synapses in aged Pls-fed murine hippocampus with moderate numbers of synaptic vesicles (C,D). Bars = 1 μm.
FIGURE 4
FIGURE 4
Transcriptomics profile of hippocampus in aged Pls-fed mice. (A) A heat map shows all differentially expressed genes in aged control versus aged Pls-fed murine hippocampus based on RNA-seq (n = 4 mice per group). (B) GeneAnalytics pathway analysis of differentially expressed genes in hippocampus of aged control vs. aged Pls-fed mice, the top ten pathways are highlighted here. (C) Plasmalogen treatment changed the transcriptomics profile of hippocampus in the aged mice. (n = 4 mice per group).
FIGURE 5
FIGURE 5
Plasmalogens enhance synaptic plasticity in the hippocampus of aged mice. (A) Representative images showing the expression of synaptophysin (green) in the CA1 and DG region of mice hippocampus. (B–C) Graph showing quantification of the immunostaining of synaptophysin in the CA1 and DG region of murine hippocampus (n = 4 mice for each group), and values are presented as mean ± SEM. (D) Representative immunoblotting of synaptophysin levels and (E) graph showing quantification of synaptophysin levels. The quantification is a ratio of synaptophysin/β-tubulin levels (n = 3 mice per group), and values are presented as mean ± SD. Asterisks indicate statistical significances compared to Aged control by one-way ANOVA; significance (*p < 0.05; **p < 0.01), scale bars, 50 μm.
FIGURE 6
FIGURE 6
Plasmalogens promote neurogenesis in the aged murine hippocampus. (A) Representative fluorescence images showing neural stem cells in young control, aged control and aged Pls-fed mice of hippocampal dentate gyrus (DG). Cells are identified based on anti-Sox2 (red). DAPI indicates nuclear staining (blue). (B) graph showed quantification of Sox2+ cells among groups. (C) The real-time PCR data showed mRNA expression of Sox2 in hippocampus of young control, aged control and aged Pls-fed mice. All values are presented as mean ± SEM. Asterisks indicate statistical significances compared to Aged control by one-way ANOVA; significance (*p < 0.05; **p < 0.01; ***p < 0.001), scale bars, 50 μm n = 4 mice for each group.
FIGURE 7
FIGURE 7
Effects of plasmalogens intervention on microglia activation and inflammatory cytokines expression. (A) Immunofluorescence staining of Iba1+ microglia cells (red) in the hippocampus of young control, aged control and aged Pls-fed mice, scale bars, 50 μm. Note that microglia of aged control mice display shorter processes and diminished ramification of processes, whereas microglia of aged Pls-fed and young control show longer and ramified processes. (B) The graph bar of skeleton analysis on microglia showed that the endpoints are increased in microglia of aged Pls-fed mice. (C) Sholl analysis of the number of branches plotted as a distance from cell body (n = 30, microglial cells per experimental group). (D–F) The real-time PCR data showed mRNA expression of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 in hippocampus of young control, aged control and aged Pls-fed mice. All values are presented as mean ± SEM. Asterisks indicate statistical significances compared to Aged control by one-way ANOVA (*p < 0.05; **p < 0.01).
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