Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University

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九州大学学術情報リポジトリ

Kyushu University Institutional Repository

生理活性脂質(プラズマローゲン)による脳の防御作 用

Katafuchi, Toshihiko

Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University

Hossain, Md. Shamim

Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University

Mineno, Kurumi

Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University

Mohamed, Fatma Ali

Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University

https://doi.org/10.15017/1563861

出版情報:福岡醫學雜誌. 106 (11), pp.293-301, 2015-11-25. Fukuoka Medical Association バージョン:

権利関係:

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Review Article

Bioactive Lipids Safeguard Our Brain fromVarious Challenges

Toshihiko K

ATAFUCHI

, Md. Shamim H

OSSAIN

, Kurumi M

INENO

and Fatma Ali M

OHAMED Department of Integrative Physiology, Graduate School of Medical Sciences,

Kyushu University, Fukuoka, 812-8582, Japan

Abstract

The bioactive lipids plasmalogens (Pls), especially the ethanolamine types, PlsEtn, are found to be enriched in the central nervous system (CNS). Previous reports showed that the brain and serum Pls levels were reduced in Alzheimerʼs disease (AD). However, the role of the Pls in AD is mostly elusive.

Furthermore Pls have been suggested to have pathophysiological significance in ageing and stress responses in the CNS, which often involve neuroinflammation characterized by glial cell activation.

Focusing on these lipids function in the murine brain, we first show that Pls can ameliorate microglial activation induced by systemic inflammatory stimuli. Then their protective effects on the neuronal cell death are demonstrated. The precise mechanism of how these lipids function in the brain is now under investigation but our study will reveal the myth of these crucial lipid components in the CNS. Future study also could suggest novel therapeutics to safeguard our brain from various stresses including ageing, neuroinflammation as well as the memory disturbance in AD.

Key words:Plasmalogens. Alzheimerʼs disease. Neuroinflammation. Lipid rafts

Introduction

Plasmalogens are unique glycerophospholipids containing a vinyl-ether bond at the sn-1 site of the glycerol backbone classified as alkenylacyl glycerophospholipids, while other diacyl glycerophospholipids have ester bond at the same position. Pls are found in all mammalian tissues, in which ethanolamine Pls (PlsEtn) are much more abundant in the brain than choline Pls (PlsCho)1). Pls release polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and arachidonic acid (ARA) from thesn-2position through the activation of Pls-selective phospholipase A2 (Pls-PLA2)2). Pls are not only structural membrane components and reservoirs for second messengers, but they are also involved in membrane fusion, ion transport and cholesterol efflux1). In addition, the vinyl ether bond at the sn-1position makes Pls more susceptible to oxidative stress than corresponding ester-type glycerophospholipids to act as antioxidants3)4)

It has been reported that PlsEtn levels in the hippocampus and cortex of patients suffering from Alzheimerʼs disease (AD) have decreased to about 70% of age-matched controls5)~7). The reduction of PlsEtn levels seems to be specific since other neurodegenerative diseases such as Huntingtonʼs and Parkinsonʼs do not show any decreases in corresponding affected brain regions (the caudate nucleus and the substantia nigra, respectively)1)5). Furthermore, PlsEtn levels in serum8)9) and erythrocyte membrane10)are also shown to be decreased in AD patients depending on the severity of dementia8)9).

Corresponding Author : Toshihiko KATAFUCHI, M.D., Ph.D.

Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

TEL : + 81-92-642-6087 FAX : + 81-92-642-6093 E-mail : kataf@physiol.med.kyushu-u.ac.jp

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These findings suggest that the reduction of PlsEtn in the AD patients may be associated with the pathogenesis of AD. Nevertheless there were few reports dealing with a role of Pls in the central nervous system (CNS), probably due to the difficulty of extracting massive amounts of intact Pls. However, the development of a new method for preparing highly pure Pls11)enabled us to investigate this issue.

In the present review article first we show that peripheral administration of Pls in mice can increase Pls contents in the brain and inhibit lipopolysaccharide (LPS)-induced activation of microglia resulting in the attenuation of neuroinflammation and accumulation of β-amyloid (Aβ) protein in the hippocampus and prefrontal cortex (PFC)12). Then we demonstrate the anti-apoptotic effects of Pls in neuronal cell line and primary hippocampal neurons through the activation of Akt and ERK1/2 kinases13). Finally the possible molecular mechanisms of the Pls actions will be discussed.

Pls in the neuroinflammation

Neuroinflammation, which is associated with the pathological sign of glial cells activation with enhanced secretion of cytokines, reactive oxygen/nitrogen species (ROS/RNS) and other related substances, is a common feature of various neurodegenerative diseases like AD, Parkinsonʼs disease (PD), multiple sclerosis, and amyotrophic lateral sclerosis14). In the animal models, systemic injection of lipopolysaccharide (LPS), an endotoxin, is well known to induce neuroinflammation accompanied by accumulation of β-amyloid protein (Aβ) in adult but not young mice14)15). Although the precise mechanisms underlying the LPS-induced amyloidogenesis have not yet been determined, it is suggested that microglia play important roles in this phenomenon since proinflammatory cytokines, as well as ROS/RNS, released from activated microglia augment Aβ formation by upregulating β-secretase mRNA expression and its enzymatic activity16)17). In our previous study we found that, in addition to the activation of glial cells and A β accumulation, the Pls levels in the hippocampus and PFC decreased to 80% of the control group following LPS administration12). There seems to be several mechanisms of the reduction of Pls during neuroinflammation.

First Pls may be targeted by oxidants such as reactive oxygen/nitrogen species (ROS/RNS) because of the Pls-specific vinyl-ether bond at the sn-1 position resulting in the reduction of Pls. Second Pls may be degraded by Pls-selective PLA2, which is activated by, for example, ceramide, produced under inflammatory condition2)18). In addition, we have recently found that not only inflammatory stimuli like systemic LPS injection, but also ageing and stress insult reduce brain Pls content to about 80% of the control groups through the down regulation of a key enzyme for de novo synthesis of Pls, glyceronephosphate O-acyltransferase (GNPAT), in an NF-κB dependent way (our unpublished data).

Interestingly the LPS-induced activation of glial cells in the PFC was blocked by coadministration of Pls (Fig. 1). This effect was also observed in the hippocampus. Furthermore the enhanced expression of IL-1 β and TNF-α mRNAs, accumulation of Aβ proteins (Fig. 2) as well as decreases in the PlsEtn levels in the hippocampus and PFC were all prevented by coadministration of Pls12), suggesting that supplementation with Pls could improve those pathological disorders. The most important question may be whether peripheral Pls can enter into the brain. So far, there are no reports indicating that Pls directly cross the blood‒brain barrier (BBB). However, a member of the major facilitator superfamily, Mfsd2a, has been shown to be the major transporter for lyso-type glycerophospholipids uptake into the brain, being expressed exclusively in endothelium of microvessels of the BBB and, interestingly, lysoplasmalogens are found to be strong competitors against other lysoglycerophospholipids19).

The precise mechanisms of the Pls inhibition of the LPS-induced glial activation are still unknown. LPS is well known ligand for toll like receptor 4 (TLR4) which is highly expressed in the glial cells20). LPS treatments directly activate TLR4 by recruiting Myd88 proteins, resulting in the dissociation of inhibitory

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A

B

Fig. 1 Activation of glial cells in the murine PFC following LPS injection (i.p.) performed on seven consecutive days and suppression by Pls applied immediately after each LPS injection.

(A)Iba-1-positive microglia (green) and GFAP-posi- tive astrocytes (red). The number and intensity of immunoreactivity of microglia increased after LPS treatment (d) with hypertrophy (dʼ) compared with that observed in the Con group (a and aʼ) and was suppressed by application of Pls (g and gʼ). The Pls group (j and jʼ) showed no differences from the Con group. GFAP-positive astrocytes also demonstrated increases in number and intensity due to LPS and suppression by Pls (middle column). Iba-1 and GFAP immunostaining did not merge with each other (f).

Scale bar : low magnification, 100 μm, and high magnification, 20 μm.

(B) A summary of LPS-induced increases in the numbers of microglia (left) and astrocytes (right) and suppression by Pls (each bar, n = 8). **, P < 0.01, respectively. Con, control ; GFAP, glial fibrillary acidic protein ; LPS, lipopolysaccharide ; PFC, prefron- tal cortex ; Pls, plasmalogens. (from Reference 12 ; Ifuku M et al. J Neuroinflammation 9 : 197, 2012. doi : 10.1186/1742-2094-9-197)

Fig. 2 Accumulation of Aβ proteins following LPS (i.p.) injection and suppression by Pls in the murine CA1 region of the hippocampus.

Neurons were stained with NeuN (red). A weak fluorescence for Aβ3-16immunoreactivity (green) in the Con group (b) increased following LPS treatment (e) and was markedly attenuated by Pl administration (h). The Aβ3-16

fluorescence merged with the NeuN immunoreactivity, indicating the intracellular localization of Aβ (f and i). Scale bar : 50 μm. Aβ, β-amyloid ; Con, control ; i.p., intraperitoneal ; LPS, lipopolysaccharide ; Pls, plasmalogens. (from Reference 12 ; Ifuku M et al. J Neuroinflammation 9 : 197, 2012. doi : 10.1186/1742-2094-9-197)

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κB protein from the p65/p50 protein complex, called NF-κB, and induce NF-κB-mediated pro-inflammatory gene expression21) (Fig. 3). Translocation of p65 and p50 protein complex into the nucleus is a sign of NF-κB activation because these protein complexes can bind onto the various gene promoter regions in this cellular compartment to transactivate their transcription. Various pro-inflamma- tory gene expression are directly regulated by NF-κB e.g., IL-1β, TNF-α and iNOS, etc.22). In our ongoing experiments data shows that Pls have the ability to inhibit nuclear translocation of NF-κB protein in the glial cells induced by LPS-treatments (data not published) (Fig. 3), suggesting for the first time that Pls have a direct anti-inflammatory activity to inhibit NF-κB activation among glial cells. Further experiments will be necessary to prove the Pls-induced inhibition of the nuclear localization of p65/p50 protein complexes.

Pls in the prevention of neuronal cell death

The findings that Pls are reduced in the brain of AD patients5)~7) suggest a possibility that normal content of brain Pls is necessary for proper function of neuronal cell. A significant loss of neuronal cells and the reduction of hippocampal volume have been attributed in the AD patient brain23)and we hypothesized that Pls might have a role to prevent neuronal cell death. Though the activation of Caspase-9, a death signals often associated with the AD brain24), is considered as a cause of neuronal cell death, the precise reasons for Caspase-9 activation and neuronal loss in AD patientʼs brain are still enigma. Activation of Caspase-9 is the downstream event of mitochondrial membrane abnormalities24) and it leads to the activation of Caspase-3 followed by the cleavages of poly ADP-ribose polymerase-1 (PARP-1) proteins that causes the DNA fragmentation leading to neuronal cells death25). To validate our hypothesis that Pls have the capability to prevent neuronal cell death, we asked this issue by employing the primary mouse neuronal cell death model where the mitochondria-mediated apoptosis occurred by nutrient deprivation13). Interestingly, we first found that Pls-treatments rescued the nutrient-deprived neuronal cell death and

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p65 p50 p65 p50 p65 p50

Plasmalogens

IkB

p IkB

MD2 TLR4

Myd88

Pro-inflammatory factors (IL1β, iNOS, etc)

Glial activation Neuroinflammation LPS

Fig. 3 Plasmalogens inhibit nuclear localization of NF-κB (p65 and p50 protein complex) induced by LPS.

LPS treatments activate toll like receptor 4 (TLR4) and induce the recruitment with Myd88 and MD2 proteins to induce NF-κB activation. This activation is accompanied by the phosphorylation of IκB proteins to degrade it resulting in the release of active p65 and p50 protein complex. These protein complex then go to the nucleus and binds with the gene promoters to activate transcription of pro-inflammatory genes.

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prevented the activation of Caspase-9 and Caspase-313)(Fig. 4).

Several caspases are known to be associated with neuronal cell death. Caspase-12 can enhance endoplasmic reticulum (ER) -mediated apoptosis pathway and Aβ induced neurotoxicity26)27), while Caspase-8 is involved in TNF-α and Fas ligand-mediated extrinsic pathways28). However, in our study using serum starvation model, either Caspase-12 or Caspase-8 was unchanged but Caspase-9 was activated13). Caspase-9 is related to intrinsic apoptosis pathway and is associated with neuronal cell death29). Since in our experiments the cleaved Caspase-9 was increased significantly upon serum starvation, which was effectively suppressed by the addition of Pls, it was suggested that Pls inhibited intrinsic apoptotic pathway to cancel serum starvation-mediated neuronal cell death.

To the question how Pls prevented the death signaling in the neuronal cells, we identified that Pls activated the Akt and ERK survival signaling (Fig. 4)13). The Akt and ERK kinases are well known to prevent neuronal cell death by modulating the Bcl-2 and Bax activity on the mitochondrial membrane30)31). It is therefore possible that Pls can prevent the apoptotic signals by increasing the Akt and ERK activation.

Possible mechanism of the Pls effect is shown in Fig. 5. We have shown that Pls increase the phosphorylation of Akt and ERK in the neuronal cells but not in the astrocytes, suggesting that Pls effect is specific to neuronal cells13).

How do Pls work in the brain?

Our findings on Pls effects on neuroinflammation and neuronal apoptosis raised the question how these lipids function in the brain. To answer this question we tried to identify the mechanism of Pls-mediated activation of Akt and ERK signals. In our recent experiment using sucrose gradient fraction method, we have found that Pls are enriched in the lipid raft microdomain of the cell membrane, which is identified by a lipid raft marker protein, flotillin, compared with non raft fractions. Lipid rafts are originally known to be cholesterol and sphingolipid-enriched membrane microdomains floating freely in the membrane bilayer.

They concentrate and segregate membrane proteins including G-protein coupled receptors (GPCRs) and other signal molecules to induce cellular signaling including Akt and ERK32)33).

Our recent findings showing an enrichment of Pls in the raft suggest that Pls may function in the rafts.

Since several glycerophospholipids including lysophosphatidic acids and platelet-activating factor as well as some fatty acyls are reported to have their own GPCRs34), we hypothesized that some neuronal specific GPCRs might transduce the Pls signaling in the cells. To this hypothesis we first found that the Pls-induced activation of ERK1/2 was blocked by pan G-protein inhibitor, GDP-βS, in the neuronal cells and then screened several orphan GPCRs. Our recent findings have shown that few GPCRs can transduce the Pls signaling to the induction of ERK phosphorylation (data not published). It is therefore possible that Pls can function as ligands to activate the GPCRs. Further experiments are going on to prove this hypothesis and if it is true then we can explore further mechanism of how Pls function in the brain to prevent neuronal cell death and to inhibit neuroinflammation.

Conclusion

In the review we showed the possibility that Pls might function as bioactive glycerophospholipids in the brain. Pls activate Akt and ERK to inhibit neuroinflammation in the brain and protect neuronal apoptosis. It is likely that the lipid rafts play an important role in the action of Pls through GPCRs. Considering these actions of Pls in the brain we have recently decided to investigate the influence of Pls on learning and memory. Our preliminary experiments of bilateral hippocampal microinjection of lentiviruses encoding short-hairpin RNA against Pls synthesizing enzyme, GNPAT, showed that knock down of GNPAT

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ControlPls (5μg/ml)

A

0 2 4 6 8 10 12 14 16

Control Pls

P<0.001

B

C

Average cell number/4.10E4μm area

Relative DNA fragmentation

0 1 2 3 4 5 6

Control Pls

P<0.001

D Control Pls

Cleaved caspase-3 β-actin Pro-caspase-3 Cleaved caspase-9 p-ERK1/2 p-AKT (S-473)

ERK1/2 AKT

Fig. 4 Plasmalogens inhibit hippocampal neuronal cell death in vitro.

(A) Pls treatments increase the survivability of primary hippocampal neurons. On DIV3, hippocampal neurons were cultured with nutrient free medium and treated with vehicle (control) and Pls (5 μg/ml) for 72 hours. On DIV6, neuronal cells were stained by Dil (red color) and imaged by the fluorescence lifetime imaging microscope. Scale bar, 50 μm.

(B)The bars show the number of primary neurons in the specific area of randomly selected 12 different locations from each dish. The plotted data (average number ± SD) represents four independent experi- ments. Bonferroniʼs test showed a significant differ- ence between the two groups (each group, n=4, P<

0.001).

(C)DNA fragmentation assays showed a significant reduction of DNA smearing in the Pls group compared with the vehicle control group (each group, n=4, P<0.001, Bonferroniʼs test).

(D) Neuronal cell lysates (50 μg protein) of DIV6 were analyzed by western blotting. Pls treatments showed a reduction in the cleaved caspase-9 and caspase-3. Increased phosphorylation of AKT and ERK was also observed in the Pls treated primary neurons. These data represents three independent experiments. (from Reference 13; Hossain MS et al.

PloS one 8 : e83508, 2013. doi : 10.1371/journal. pone.

0083508)

Plasmalogens

Neuronal cell death Nutrient

deprivation

Cytochrome C Caspase9 Caspase3

PARP-mediated cleavage of DNA Bcl-2 Bax

Fig. 5 Plasmalogens protect neuronal cell death caused by nutrient deprivation.

Nutrient deprivation was found to induce mitochondria-dependent neuronal cell death marked by the activation of Caspase-9. Increases in pro-apoptotic protein Bax and decrease of anti-apoptotic protein Bcl-2 are known to destabilize mitochondrial membrane function leading to the release of toxic Cytochrome C. Caspase-9 can further activates Caspase-3 to release cleaved Caspase-3, resulting in the activation of poly ADP-ribose polymerase (PARP). Cleaved PARP protein can breakdown genomic DNA, leading to neuronal cell death. Plasmalogens are found to inhibit cleavages of Caspase-9.

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impaired spatial learning in mice. In addition, application of Pls enhanced expression of phosphorylated cAMP response element binding protein (CREB) and brain derived neurotrophic factor (BDNF) in the neuronal cells. These findings suggest the possible role of Pls in learning and memory process and may help to explore a novel therapeutic approach to dementia like AD.

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(和文抄録)

生理活性脂質(プラズマローゲン)による脳の防御作用

九州大学大学院医学研究院 統合生理学分野

片 渕 俊 彦,モハメド シャミン ホセイン,峰野くるみ,ファトマ アリ モハメド

グリセロリン脂質の中でも,sn-1基にビニルエーテル結合を有しヘッドグループにエタノールアミン

が結合したエタノールアミン・プラズマローゲン(Pls)は,神経系に多く存在し,種々の生理活性をもつ ことが明らかになってきた.これまでアルツハイマー病(AD)において血清および脳の Pls 含量が低下し ていることが報告されているが,その役割や意義については不明であった.一方で,老化やストレスに対 する脳の応答機序としてしばしば観察される「神経炎症」の機序において,Pls が病態生理学的意義を持っ ていることが示唆された.

われわれは Pls の脳内における役割に注目し,リポポリサッカライド(LPS)の末梢投与による脳内グリ ア細胞の活性化やβアミロイド蛋白の沈着などを特徴とする神経炎症が,Pls の同時投与で抑制されるこ とを明らかにした.さらに培養神経細胞におけるアポトーシスを Pls が抑制することが明らかになった.

その機序として,Akt や ERK などのリン酸化酵素の活性化が考えられた.さらに詳細な機序について研 究を進めているが,それによってこのグリセロリン脂質の中枢神経系における生理的意義が明らかになる.

このことは老化や様々なストレスによる神経炎症刺激による神経炎症,さらには AD における学習記憶障 害を抑制する新しい治療法にも繋がると考えられる.

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