Browsing by Subject "FATTY-ACIDS"

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  • Riederer, Monika; Ojala, Pauli J.; Hrzenjak, Andelko; Tritscher, Michaela; Hermansson, Martin; Watzer, Bernhard; Schweer, Horst; Desoye, Gernot; Heinemann, Akos; Frank, Sasa (2010)
  • Akbaraly, Tasnime; Wurtz, Peter; Singh-Manoux, Archana; Shipley, Martin J.; Haapakoski, Rita; Lehto, Maili; Desrumaux, Catherine; Kähönen, Mika; Lehtimäki, Terho; Mikkilä, Vera; Hingorani, Aroon; Humphries, Steve E.; Kangas, Antti J.; Soininen, Pasi; Raitakari, Olli; Ala-Korpela, Mika; Kivimäki, Mika (2018)
    Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations-the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 +/- 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 +/- 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.
  • Packard, Chris J.; Boren, Jan; Taskinen, Marja-Riitta (2020)
    Elevations in plasma triglyceride are the result of overproduction and impaired clearance of triglyceride-rich lipoproteins-very low-density lipoproteins (VLDL) and chylomicrons. Hypertriglyceridemia is characterized by an accumulation in the circulation of large VLDL-VLDL1-and its lipolytic products, and throughout the VLDL-LDL delipidation cascade perturbations occur that give rise to increased concentrations of remnant lipoproteins and small, dense low-density lipoprotein (LDL). The elevated risk of atherosclerotic cardiovascular disease in hypertriglyceridemia is believed to result from the exposure of the artery wall to these aberrant lipoprotein species. Key regulators of the metabolism of triglyceride-rich lipoproteins have been identified and a number of these are targets for pharmacological intervention. However, a clear picture is yet to emerge as to how to relate triglyceride lowering to reduced risk of atherosclerosis.
  • Ruskamo, Salla; Krokengen, Oda C.; Kowal, Julia; Nieminen, Tuomo; Lehtimäki, Mari; Raasakka, Arne; Dandey, Venkata P.; Vattulainen, Ilpo; Stahlberg, Henning; Kursula, Petri (2020)
    Myelin protein P2 is a peripheral membrane protein of the fatty acid?binding protein family that functions in the formation and maintenance of the peripheral nerve myelin sheath. Several P2 gene mutations cause human Charcot-Marie-Tooth neuropathy, but the mature myelin sheath assembly mechanism is unclear. Here, cryo-EM of myelin-like proteolipid multilayers revealed an ordered three-dimensional (3D) lattice of P2 molecules between stacked lipid bilayers, visualizing supramolecular assembly at the myelin major dense line. The data disclosed that a single P2 layer is inserted between two bilayers in a tight intermembrane space of ?3 nm, implying direct interactions between P2 and two membrane surfaces. X-ray diffraction from P2-stacked bicelle multilayers revealed lateral protein organization, and surface mutagenesis of P2 coupled with structure-function experiments revealed a role for both the portal region of P2 and its opposite face in membrane interactions. Atomistic molecular dynamics simulations of P2 on model membrane surfaces suggested that Arg-88 is critical for P2-membrane interactions, in addition to the helical lid domain. Negatively charged lipid headgroups stably anchored P2 on the myelin-like bilayer surface. Membrane binding may be accompanied by opening of the P2 ?-barrel structure and ligand exchange with the apposing bilayer. Our results provide an unprecedented view into an ordered, multilayered biomolecular membrane system induced by the presence of a peripheral membrane protein from human myelin. This is an important step toward deciphering the 3D assembly of a mature myelin sheath at the molecular level.
  • Kiiski, Iiro; Ollikainen, Elisa; Artes, Sanna; Järvinen, Päivi; Jokinen, Ville; Sikanen, Tiina (2021)
  • Tuunainen, Petra; Koivunen, Erja; Valaja, Jarmo; Valkonen, Eija; Hiidenhovi, Jaakko; Tupasela, Tuomo; Hongisto, Marja (2016)
    Performance, meat quality and litter quality were determined in 4000 male and female Ross 308 broilers fed on starter diet (soybean meal or rapeseed meal and peas) and grower-finisher diets based on either soybean meal (control) or substituting rapeseed meal or rapeseed meal and pea in different proportions (100/0%, 75/25% or 50/50%) for soybean meal in iso-nitrogenous basis. Performance of the birds fed with soybean meal diets was superior compared to that of the birds fed with rapeseed meal and pea based diets. Bird performance was the poorest and mortality the highest for the birds fed with the rapeseed meal grower diet. In this experiment birds did not reach performance target for the age and strain of bird. Overall, diet based solely on rapeseed meal protein is not suitable for broiler production. However, dietary rapeseed meal inclusion clearly improved fatty acid profile of breast meat. The omega-6/omega-3-ratio was 4.1, 2.4 and 2.7 for soybean meal, rapeseed meal, and rapeseed meal and peas based diets, respectively. There were no differences in sensory quality evaluation of breast meat between the treatments.
  • Verni, Michela; Rizzello, Carlo Giuseppe; Coda, Rossana (2019)
    Cereals are one of the major food sources in human diet and a large quantity of by-products is generated throughout their processing chain. These by-products mostly consist of the germ and outer layers (bran), deriving from dry and wet milling of grains, brewers’ spent grain originating from brewing industry, or others originating during bread-making and starch production. Cereal industry by-products are rich in nutrients, but still they end up as feed, fuel, substrates for biorefinery, or waste. The above uses, however, only provide a partial recycle. Although cereal processing industry side streams can potentially provide essential compounds for the diet, their use in food production is limited by their challenging technological properties. For this reason, the development of innovative biotechnologies is essential to upgrade these by-products, potentially leading to the design of novel and commercially competitive functional foods. Fermentation has been proven as a very feasible option to enhance the technological, sensory, and especially nutritional and functional features of the cereal industry by-products. Through the increase of minerals, phenolics and vitamins bioavailability, proteins digestibility, and the degradation of antinutritional compounds as phytic acid, fermentation can lead to improved nutritional quality of the matrix. In some cases, more compelling benefits have been discovered, such as the synthesis of bioactive compounds acting as antimicrobial, antitumoral, antioxidant agents. When used for baked-goods manufacturing, fermented cereal by-products have enhanced their nutritional profile. The key factor of a successful use of cereal by-products in food applications is the use of a proper bioprocessing technology, including fermentation with selected starters. In the journey toward a more efficient food chain, biotechnological approaches for the valorization of agricultural side streams can be considered a very valuable help.
  • Tuomisto, Jouni; Asikainen, Arja; Meriläinen, Päivi; Haapasaari, Päivi (2020)
    Background: Health risks linked with dioxin in fish remain a complex policy issue. Fatty Baltic fish contain persistent pollutants, but they are otherwise healthy food. We studied the health benefits and risks associated with Baltic herring and salmon in four countries to identify critical uncertainties and to facilitate an evidence-based discussion. Methods: We performed an online survey investigating consumers’ fish consumption and its motivation in Denmark, Estonia, Finland, and Sweden. Dioxin and methylmercury concentrations were estimated based on Finnish studies. Exposure-response functions for several health endpoints were evaluated and quantified based on the scientific literature. We also quantified the infertility risk of men based on a recent European risk assessment estimating childhood dioxin exposure and its effect on sperm concentration later in life. Results: Baltic herring and salmon contain omega-3 fatty acids and vitamin D, and the beneficial impact of these fishes on cardiovascular diseases, mortality, and the risk of depression and cancer clearly outweighs risks of dioxins and methylmercury in people older than 45 years of age and in young men. Young women may expose their children to pollutants during pregnancy and breast feeding. This study suggests that even in this critical subgroup, the risks are small and the health benefits are greater than or at least similar to the health risks. Value of information analysis demonstrated that the remaining scientific uncertainties are not large. In contrast, there are several critical uncertainties that are inherently value judgements, such as whether exceeding the tolerable weekly intake is an adverse outcome as such; and whether or not subgroup-specific restrictions are problematic. Conclusions: The potential health risks attributable to dioxins in Baltic fish have more than halved in the past 10 years. The new risk assessment issued by the European Food Safety Authority clearly increases the fraction of the population exceeding the tolerable dioxin intake, but nonetheless, quantitative estimates of net health impacts change only marginally. Increased use of small herring (which have less pollutants) is a no-regret option. A more relevant value-based policy discussion rather than research is needed to clarify official recommendations related to dioxins in fish.
  • Chernikova, Tatyana; Bargiela, Rafael; Toshchakov, Stepan V.; Shivaraman, Vignesh; Lunev, Evgenii A.; Yakimov, Michail M.; Thomas, David Neville; Golyshin, Peter N. (2020)
    Marine hydrocarbon-degrading bacteria play an important role in natural petroleum biodegradation processes and were initially associated with man-made oil spills or natural seeps. There is no full clarity though on what, in the absence of petroleum, their natural niches are. Few studies pointed at some marine microalgae that produce oleophilic compounds (alkanes, long-chain fatty acids, and alcohols) as potential natural hosts of these bacteria. We established Dansk crude oil-based enrichment cultures with photobioreactor-grown marine microalgae cultures Pavlova lutheri and Nannochloropsis oculata and analyzed the microbial succession using cultivation and SSU (16S) rRNA amplicon sequencing. We found that petroleum enforced a strong selection for members of Alpha- and Gamma-proteobacteria in both enrichment cultures with the prevalence of Alcanivorax and Marinobacter spp., well-known hydrocarbonoclastic bacteria. In total, 48 non-redundant bacterial strains were isolated and identified to represent genera Alcanivorax, Marinobacter, Thalassospira, Hyphomonas, Halomonas, Marinovum, Roseovarius, and Oleibacter, which were abundant in sequencing reads in both crude oil enrichments. Our assessment of public databases demonstrated some overlaps of geographical sites of isolation of Nannochloropsis and Pavlova with places of molecular detection and isolation of Alcanivorax and Marinobacter spp. Our study suggests that these globally important hydrocarbon-degrading bacteria are associated with P. lutheri and N. oculata.
  • Siren, Reijo; Eriksson, Johan G.; Peltonen, Markku; Vanhanen, Hannu (2014)
  • de Mello, Vanessa D.; Paananen, Jussi; Lindstrom, Jaana; Lankinen, Maria A.; Shi, Lin; Kuusisto, Johanna; Pihlajamaki, Jussi; Auriola, Seppo; Lehtonen, Marko; Rolandsson, Olov; Bergdahl, Ingvar A.; Nordin, Elise; Ilanne-Parikka, Pirjo; Keinanen-Kiukaanniemi, Sirkka; Landberg, Rikard; Eriksson, Johan G.; Tuomilehto, Jaakko; Hanhineva, Kati; Uusitupa, Matti (2017)
    Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of alpha-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.
  • Gerl, Mathias J.; Klose, Christian; Surma, Michal A.; Fernandez, Celine; Melander, Olle; Männistö, Satu; Borodulin, Katja; Havulinna, Aki S.; Salomaa, Veikko; Ikonen, Elina; Cannistraci, Carlo V.; Simons, Kai (2019)
    Obesity is associated with changes in plasma lipids, but while simple lipid quantification is routinely used, plasma lipids are rarely investigated at the level of individual molecules. A machine learning study based on lipidomes of a total of 1,311 individuals reveals improved associations of plasma lipids with total body fat and fat distribution compared to routine clinical laboratory variables.
  • Wurtz, Peter; Cook, Sarah; Wang, Qin; Tiainen, Mika; Tynkkynen, Tuulia; Kangas, Antti J.; Soininen, Pasi; Laitinen, Jaana; Viikari, Jorma; Kahonen, Mika; Lehtimaki, Terho; Perola, Markus; Blankenberg, Stefan; Zeller, Tanja; Mannisto, Satu; Salomaa, Veikko; Jarvelin, Marjo-Riitta; Raitakari, Olli T.; Ala-Korpela, Mika; Leon, David A. (2016)
    Background: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults. Methods: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24-45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. Results: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P<0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R-2 = 0.83, slope = 0.7260.04). Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.
  • Lauren, Eva; Tigistu-Sahle, Feven; Valkonen, Sami; Westberg, Melissa; Valkeajarvi, Anne; Eronen, Juha; Siljander, Pia R-M; Pettila, Ville; Kakela, Reijo; Laitinen, Saara; Kerkela, Erja (2018)
    Red blood cells (RBCs) are stored up to 35-42 days at 2-6 degrees C in blood banks. During storage, the RBC membrane is challenged by energy depletion, decreasing pH, altered cation homeostasis, and oxidative stress, leading to several biochemical and morphological changes in RBCs and to shedding of extracellular vesicles (EVs) into the storage medium. These changes are collectively known as RBC storage lesions. EVs accumulate in stored RBC concentrates and are, thus, transfused into patients. The potency of EVs as bioactive effectors is largely acknowledged, and EVs in RBC concentrates are suspected to mediate some adverse effects of transfusion. Several studies have shown accumulation of lipid raft associated proteins in RBC EVs during storage, whereas a comprehensive phospholipidomic study on RBCs and corresponding EVs during the clinical storage period is lacking. Our mass spectrometric and chromatographic study shows that RBCs maintain their major phospholipid (PL) content well during storage despite abundant vesiculation. The phospholipidomes were largely similar between RBCs and EVs. No accumulation of raft lipids in EVs was seen, suggesting that the primary mechanism of RBC vesiculation during storage might not be raft-based. Nonetheless, a slight tendency of EV PLs for shorter acyl chains was observed.
  • Munsch-Alatossava, Patricia; Käkelä, Reijo; Ibarra, Dominique; Youbi-Idrissi, Mohammed; Alatossava, Tapani (2018)
    Cold storage aims to preserve the quality and safety of raw milk from farms to dairies; unfortunately, low temperatures also promote the growth of psychrotrophic bacteria, some of which produce heat-stable enzymes that cause spoilage of milk or dairy products. Previously, N-2 gas flushing of raw milk has demonstrated significant potential as a method to hinder bacterial growth at both laboratory and pilot plant scales. Using a mass spectrometry-based lipidomics approach, we examined the impact of cold storage [at 6 degrees C for up to 7 days, the control condition (C)], on the relative amounts of major phospholipids (phosphatidylethanolamine/PE, phosphatidylcholine/PC, phosphatidylserine/PS, phosphatidylinositol/PI, and sphingomyelin/SM) in three bovine raw milk samples, and compared it to the condition that received additional N-2 gas flushing (N). As expected, bacterial growth was hindered by the N-2-based treatment (over 4 log-units lower at day 7) compared to the non-treated control condition. At the end of the cold storage period, the control condition (C7) revealed higher hydrolysis of PC, SM, PE, and PS (the major species reached 27.2, 26.7, 34.6, and 9.9 mu M, respectively), compared to the N-2-flushed samples (N7) (the major species reached 55.6, 35.9, 54.0, and 18.8 mu M, respectively). C7 samples also exhibited a three-fold higher phosphatidic acid (PA) content (6.8 mu M) and a five-fold higher content (17.3 mu M) of lysophospholipids (LPE, LPC, LPS, and LPI) whereas both lysophospholipids and PA remained at their initial levels for 7 days in N7 samples. Taking into consideration the significant phospholipid losses in the controls, the lipid profiling results together with the microbiological data suggest a major role of phospholipase (PLase) C (PLC) in phospholipolysis during cold storage. However, the experimental data also indicate that bacterial sphingomyelinase C, together with PLases PLD and PLA contributed to the degradation of phospholipids present in raw milk as well, and potential contributions from PLB activity cannot be excluded. Altogether, this lipidomics study highlights the beneficial effects of N-2 flushing treatment on the quality and safety of raw milk through its ability to effectively hinder phospholipolysis during cold storage.
  • Laasonen, Marja; Lahti-Nuuttila, Pekka; Leppämäki, Sami; Tani, Pekka; Wikgren, Jan; Harno, Hanna; Oksanen-Hennah, Henna; Pothos, Emmanuel; Cleeremans, Axel; Dye, Matthew W. G.; Cousineau, Denis; Hokkanen, Laura (2020)
    Two themes have puzzled the research on developmental and learning disorders for decades. First, some of the risk and protective factors behind developmental challenges are suggested to be shared and some are suggested to be specific for a given condition. Second, language-based learning difficulties like dyslexia are suggested to result from or correlate with non-linguistic aspects of information processing as well. In the current study, we investigated how adults with developmental dyslexia or ADHD as well as healthy controls cluster across various dimensions designed to tap the prominent non-linguistic theories of dyslexia. Participants were 18-55-year-old adults with dyslexia (n= 36), ADHD (n= 22), and controls (n= 35). Non-linguistic theories investigated with experimental designs included temporal processing impairment, abnormal cerebellar functioning, procedural learning difficulties, as well as visual processing and attention deficits. Latent profile analysis (LPA) was used to investigate the emerging groups and patterns of results across these experimental designs. LPA suggested three groups: (1) a large group with average performance in the experimental designs, (2) participants predominantly from the clinical groups but with enhanced conditioning learning, and (3) participants predominantly from the dyslexia group with temporal processing as well as visual processing and attention deficits. Despite the presence of these distinct patterns, participants did not cluster very well based on their original status, nor did the LPA groups differ in their dyslexia or ADHD-related neuropsychological profiles. Remarkably, the LPA groups did differ in their intelligence. These results highlight the continuous and overlapping nature of the observed difficulties and support the multiple deficit model of developmental disorders, which suggests shared risk factors for developmental challenges. It also appears that some of the risk factors suggested by the prominent non-linguistic theories of dyslexia relate to the general level of functioning in tests of intelligence.
  • Hemida, Manal B. M.; Salin, Siru; Vuori, Kristiina A.; Moore, Robin; Anturaniemi, Johanna; Rosendahl, Sarah; Barrouin-Melo, Stella Maria; Hielm-Bjorkman, Anna (2021)
    Background The increased prevalence of atopic dermatitis (AD) in dogs necessitates research in its disease etiology. Objectives To explore the association between puppyhood dietary exposures and prevalence of owner-reported allergy/atopy skin signs (AASS) after the age of 1 year. Animals Four thousand and twenty-two dogs were eligible, 1158 cases, and 2864 controls. Methods This cross-sectional hypothesis-driven observational study was extracted from the DogRisk food frequency questionnaire. Forty-six food items and the ratio of 4 major diet types were tested for their association with AASS incidence later in life. Potential puppyhood dietary risk factors for AASS incidence were specified using binary multivariable logistic regression. The model was adjusted for age and sex. Results Eating raw tripe (odds ratio, 95% confidence intervals OR, 95% CI = 0.36, 0.16-0.79; P = .01), raw organ meats (OR, 95% CI = 0.23, 0.08-0.67; P = .007), human meal leftovers, and fish oil supplements as well as eating more that 20% of the diet as raw and/or
  • Robciuc, Marius R.; Tahvanainen, Esa; Jauhiainen, Matti; Ehnholm, Christian (2010)
  • Javanainen, Matti; Enkavi, Giray; Guixa-Gonzalez, Ramon; Kulig, Waldemar; Martinez-Seara, Hector; Levental, Ilya; Vattulainen, Ilpo (2019)
    G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling. Author summary Our current picture of cellular membranes depicts them as laterally heterogeneous sheets of lipids crowded with membrane proteins. These proteins often require a specific lipid environment to efficiently perform their functions. Certain neuroreceptor proteins are regulated by membrane cholesterol that is considered to be enriched in ordered membrane domains. In the brain, these very same domains also contain a fair amount of polyunsaturated fatty acids (PUFAs) that have also been discovered to interact favorably with many receptor proteins. However, certain neurological diseasesassociated with the inadequate functioning of the neuroreceptorsseem to result in the decrease of brain PUFA levels. We hypothesized that this decrease in PUFA levels somehow inhibits receptor partitioning to cholesterol-rich domains, which could further compromise their function. We verified our hypothesis by an extensive set of computer simulations. They demonstrated that the PUFA-receptor interaction indeed leads to favorable partitioning of the receptors in the cholesterol-rich ordered domains. Moreover, the underlying mechanism based on the shielding of the rough protein surface by the PUFAs seems to be exclusive for multi-helical protein structures, of which neuroreceptors are a prime example.
  • Merezhko, Maria; Brunello, Cecilia A.; Yan, Xu; Vihinen, Helena; Jokitalo, Eija; Uronen, Riikka-Liisa; Huttunen, Henri J. (2018)
    Tauopathies are characterized by cerebral accumulation of Tau protein aggregates that appear to spread throughout the brain via a cell-to-cell transmission process that includes secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. Here, we show that phosphorylated, oligomeric Tau clusters at the plasma membrane in N2A cells and is secreted in vesicle-free form in an unconventional process sensitive to changes in membrane properties, particularly cholesterol and sphingomyelin content. Cell surface heparan sulfate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Notably, secretion of endogenous Tau from primary cortical neurons is mediated, at least partially, by a similar mechanism. We suggest that Tau is released from cells by an unconventional secretory mechanism that involves its phosphorylation and oligomerization and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane.