scholarly journals α-Linolenic acid induces clearance of Tau seeds via Actin-remodeling in Microglia

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Fatty Acids ◽  
Linolenic Acid ◽  
Dietary Supplement ◽  
Actin Polymerization ◽  
Immune Cell ◽  
Amyloid Β ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Actin Remodeling ◽  
Membrane Ruffling

AbstractAlzheimer’s disease (AD) is known by characteristic features, extracellular burden of amyloid-β and intracellular neuronal Tau. Microglia, the innate immune cell of the brain has the ability to clear the burden of accumulated proteins via phagocytosis. But the excessive proinflammatory cytokine production, altered cellular signaling and actin remodeling hampers the process of migration and phagocytosis by microglia. Actin remodeling is necessary to initiate the chemotactic migration of microglia towards the target and engulf it. The formation of lamellipodia, filopodia, membrane ruffling and rapid turnover of F-actin is necessary to sense the extracellular target by the cells. Omega-3 fatty acids, are known to impose anti-inflammatory phenotype of microglia by enhancing its ability for migration and phagocytosis. But the role of omega-3 fatty acids in cellular actin remodeling, which is the basis of cellular functions such as migration and phagocytosis, is not well understood. Here, we have focused on the effect of dietary supplement of α-linolenic acid (ALA) on extracellular Tau internalization and assisted actin polymerization for the process. ALA is found to induce membrane ruffling and phagocytic cup formation along with cytoskeletal rearrangement. ALA also enhances the localization of Arp2/3 complex at the leading edge and its colocalization with F-actin to induce the actin polymerization. The excessive actin polymerization might help the cell to protrude forward and perform its migration. The results suggest that dietary supplement of ALA could play a neuroprotective role and slow down the AD pathology.

scholarly journals α-Linolenic acid induces clearance of Tau seed via Actin-remodeling in Microglia

2020 ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Fatty Acids ◽  
Inflammatory Response ◽  
Dietary Supplement ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Cellular Functions ◽  
Actin Remodeling ◽  
Membrane Ruffling ◽  
Anti Inflammatory

Abstract Background Tau seeds exhibit a detrimental role in the spread of disease in Alzheimer’s disease. These species are found to be neurotoxic and activate microglia. However, the activation of microglia in pro-inflammatory response further elevates neurodegeneration. Omega-3 dietary fatty acids, on the other hand; exert an anti-inflammatory response by microglia. Along with the receptor expression, omega-3 fatty acids influence various important cellular functions. The role of omega-3 fatty acids on actin remodeling, which is the basis of cellular functions such as migration and phagocytosis is not known. Here in this study, we focus on effect of dietary supplement of ALA on extracellular Tau internalization and assisted actin polymerization for the process. ALA is found to induce membrane ruffling and phagocytic cup formation along with cytoskeletal rearrangement to induce lamellipodia and filopodia at the front end to move forward and assist the cell to identify the target. ALA is observed to promote the internalization of Tau and necessary actin remodeling for phagocytosis. Methods α-Linolenic (ALA) acid has been used for the study. ALA was dissolved in 100% ethanol and solubilized at 50°C for 2 hours. The human Tau aggregates was prepared in vitro for the internalization study in microglia in presence of α-Linolenic acids (ALA) via fluorescence microscopy with Apotome. The studied the role α-Linolenic acids (ALA) actin remodeling in cellular processes in presence of Tau seed. The study of actin structures lamellipodia, filopodia, and membrane ruffling along with Iba-1 and Arp2/3 complex was observed on ALA exposure. Results Extracellular Tau species are found to internalize more presence of ALA in microglia. The extensive polarization and migration was observed as indicated by extensive lamellipodia and filopodia formation. The formation of extensive actin branching in lamellipodia and membrane ruffling was studied with the help of ARP2/3 complex for nucleating actin network. The high density of ARP2/3 complex at the leading ends of migratory microglia confirmed the extensive branching of actin filaments on ALA exposure. Enhanced formation of lamellipodia and filopodia helps in migration and internalization of tau seed. The actin dynamics supports the phagocytosis process. Conclusion Our approach provides the insights of beneficial role of ALA as anti-inflammatory dietary supplement to treat AD. ALA induces internalization of Tau and necessary actin remodeling for phagocytosis.

scholarly journals α- Linoleanic acid modulates phagocytosis of extracellular Tau and induces microglial migration by actin-remodeling

2020 ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Fatty Acids ◽  
Cell Membrane ◽  
Dietary Fatty Acids ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Actin Remodeling ◽  
Membrane Ruffling ◽  
Intracellular Degradation ◽  
Anti Inflammatory

Abstract Background Seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer’s disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory property to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascade and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy.Method N9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α- Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were assessed by wound-scratch assay along with Microtubule organizing center (MTOC) reorientation were studied after exposure of Tau and ALA as the property of highly migratory microglia. The role of actin in phagocytosis and migration was observed with the study of actin structures lamellipodia, filopodia, and membrane ruffling. The formation of extensive actin branching in lamellipodia and membrane ruffling was studied with the help of ARP2/3 complex for nucleating actin network.Results The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increase levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization and reduces the nuclear-centrosomal axis polarity and favorable anterior positioning of MTOC. The increased migration also complememnted with the enhance actin remodeling through lamellipodia, filopodia and membrane ruffles formation along with Iba-1 protein. The high desnity of ARP2/3 complex at the leading ends of migratory microglia confirmed the extensive branching of actin filaments on ALA exposure.Conclusions Tau seeds greatly contributes to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhance phagocytosis and intracellular degradation of internalized Tau. The actin dynamics and enhanced migration supports the phagocytosis process. Our approach provides the insights of beneficial role of ALA as anti-inflammatory dietary supplement to treat AD.

scholarly journals Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review

2020 ◽  
Vol 37 (2) ◽  
pp. 656-670 ◽  
Author(s):  
Daniel E. Hilleman ◽  
Barbara S. Wiggins ◽  
Michael B. Bottorff
Keyword(s):  
Fatty Acids ◽  
Dietary Supplement ◽  
Narrative Review ◽  
Omega 3 Fatty Acids ◽  
Omega 3

scholarly journals α- Linolenic Acid Modulates Phagocytosis of Extracellular Tau and Induces Microglial Migration

2020 ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Fatty Acids ◽  
Cell Membrane ◽  
Linolenic Acid ◽  
Dietary Fatty Acids ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Microtubule Organizing Center ◽  
Intracellular Degradation ◽  
Organizing Center ◽  
Anti Inflammatory

Abstract Background The seeding effect of extracellular Tau species is an emerging aspect to study the Tauopathies in Alzheimer’s disease. Tau seeds enhance the propagation of disease along with its contribution to microglia-mediated inflammation. Omega-3 fatty acids are known to exert the anti-inflammatory property to microglia by modulating cell membrane compositions. The immunomodulatory function of omega-3 fatty acids exerts anti-inflammatory properties to microglia. Owing to the imparted anti-inflammatory nature enhance phagocytosis and increased migration property has been observed in microglia. The dietary omega-3 fatty acids are found to change the lipid composition of the cell membrane that predominated many signaling cascades and by modulating specific receptor response. Thus the omega-3 fatty acids influence microglial response in Tauopathy. Methods N9 microglia cells were exposed to extracellular full-length Tau monomer and aggregates along with ALA (α- Linolenic acid) to study the internalization of exposed Tau. The degradation of internalized Tau studied with the endosomal markers Rab5 and Rab7. The final degradation step in phagocytosis has been studied with LAMP-2A as lysosomal markers. The changes in the rate of migration of microglia were assessed by wound-scratch assay along with Microtubule organizing center (MTOC) reorientation were studied after exposure of Tau and ALA as the property of highly migratory microglia. Results The increased phagocytosis of extracellular Tau monomer and aggregates has been observed upon ALA exposure to microglia cells. The intracellular degradation of internalized Tau species was targeted by early and late endosomal markers Rab5 and Rab7. The increased levels of LAMP-2A and colocalization with internalized Tau indicated the degradation via lysosome. These results indicate the degradation of internalized Tau species in the presence of ALA instead of getting accumulated in the cell. The enhanced migratory ability of microglia in the presence of ALA induces the MTOC repolarization and reduces the nuclear-centrosomal axis polarity and favorable anterior positioning of MTOC. Conclusions Tau seeds greatly contribute to the spread of disease, one way to reduce the spreading is to reduce the presence of extracellular Tau seed. Microglia could be influenced to reduce extracellular Tau seed with dietary fatty acids. Our results suggest that dietary fatty acids ALA significantly enhances phagocytosis and intracellular degradation of internalized Tau. Enhanced migration supports the phagocytosis process. Our approach provides insights into the beneficial role of ALA as an anti-inflammatory dietary supplement to treat AD.

THE EFFECT OF OMEGA 3 FATTY ACIDS ON MEGAKARYOCYTE ARACHIDONIC ACID METABOLISM

1987 ◽  
Author(s):  
Paul K Schick ◽  
Barbara P Schick ◽  
Pat Webster
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Linolenic Acid ◽  
Acid Metabolism ◽  
Striking Difference ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Marine Oils ◽  
Lipid Species

Dietary omega 3 polyunsaturated fatty acids are thought to prevent atherosclerosis. It has been proposed that omega 3 fatty acids modify platelet arachidonic acid (20:4) metabolism and platelet function and thereby reduce the incidence of thrombosis. We have previously shown that megakaryocytes (MK), like platelets, contain large amounts of esterified 20:4. The study addresses the following questions: 1) Do omega 3 fatty acids have a primary action on 20:4 metabolism in MK rather than in platelets. 2) Do omega 3 marine oils, docosahexaenoic acid (22:6) and eicosapentaenoic acid (20:5), have a different effect on megakaryocyte 20:4 metabolism than does alpha linolenic acid (18:3), the major omega-3 fatty acid present in normal diets? 3) How do omega-3 fatty acids modify megakaryocyte 20:4 acid metabolism? MK and platelets were isolated from guinea pigs. Isolated cells were incubated with radiolabeled 20:4 acid and unlabeled 18:3, 20:5 or 22:6. Incubations were terminated by lipid extraction, lipid classes were separated by thin-layer chromatography and the incorporation of radiolabeled 20:4 into lipid species was measured by scintillation spectrometry.MK (106) can incorporate about 4 times more 20:4 than 109 platelets. We have previously shown that 20:4 is incorporated into all endogenous pools of 20:4 in MK while platelets appear to have a limited capacity to incorporate 20:4 into phosphatidyl-ethanolamine (PE). Marine oils, 22:6 and 20:5, had similar effects on the incorporation of radiolabeled 20:4 in MK. Both marine oils reduced the total uptake of 20:4 in megakaryocytes but the reduction occured primarily in PE and phosphatidylserine (PS) rather than in phosphatidylcholine (PC) and phosphatidylinositol (PI). Both 20:5 and 22:6 caused a 50% reduction in the incorporation of radiolabeled 20:4 into megakaryocyte PE and PS while only a 20% reduction into PC and PI. There was a striking difference in the effect of 18:3. Even though the incubation of megakaryocytes with 18:3 reduced the uptake of 20:4, the distribution of the incorporated 20:4 in phospholipids of megakaryocytes incubated with 18:3 was similar to that in controls. Thus, 18:3 did not have a selective effect on the incorporation of 20:4 into PE or PS. Whereas megakaryocyte 20:4 metabolism was significantly affected by omega-3 fatty acids, the incubation of guinea pig or human platelets with 22:6, 20:5 or 18:3 did not result in any alteration of the incorporation of 20:4 into platelet phospholipids.20:4 may be initially incorporated into megakaryocyte PC and subsequently transfered to PE and other phospholipids. Omega 3 marine oils, 20:5 and 22:6, appear to have a selective action on the incorporation or transfer of 20:4 into PE and PS. One mechanism for these observations would be an effect of marine oils on megakaryocyte acyltransferase and/or transacylases. Omega 3 linolenic acid appears to reduce the uptake of 20:4 but does not affect the transfer of 20:4 into PE and PS since there was no selective inhibition of uptake into PE or other megakaryocyte phospholipids. The observation that marine oils did not have any effect on 20:4 metabolism in platelets indicated that omega 3 polyunsaturated fatty acids primarily affect megakaryocytes. This phenomenon may result in the production of platelets with abnormal content and compartmentalization of arachidonic acid. The localization of 20:4 in different pools in these platelets could influence the availability of esterified 20:4 for the production of thromboxanes and other eicosanoids. Another implication of the study is that omega 3 fatty acids may have a greater effect on precursor cells than on differentiated cells and tissues and influence cellular maturation.

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