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AimsNon-targeted lipidomics analysis was conducted in post-mortem human frontal cortex area 8 (GM) and white matter of the frontal lobecentrum semi-ovale(WM) to identify lipidomes in middle-aged individuals with no neurofibrillary tangles and senile plaques, and cases at progressive stages of sporadic Alzheimer’s disease (sAD).MethodsLipidomic analysis using an LC-MS/MS platform was carried out in selected cases with suitable post-mortem lacking co-morbidities and concomitant brain pathologies. Complementary data were obtained using RT-qPCR and immunohistochemistry.ResultsThe WM shows an adaptive lipid phenotype resistant to lipid peroxidation, characterized by a lower fatty acid unsaturation, peroxidizability index, and higher ether lipid content than the GM. Changes in the lipidomic profile more marked in the WM than in GM occur in AD with disease progression. WM alterations are characterized by a decline in the content of branched fatty acid esters of hydroxy fatty acids (FAHFA), diacylglycerols (DG), triacylglycerols (TG), glycerophospholipids (GP) (especially ether lipids), and sphingolipids (especially sulfatides, ceramides, and glycosphingolipids). The GM acquires a fatty acid profile prone to peroxidation in sAD, while WM reinforces its peroxidation-resistant trait. Transcriptomic data point to additional defects of peroxisomal function.ConclusionsFour functional categories are associated with the different lipid classes affected in sAD: membrane structural composition, bioenergetics, antioxidant protection, and bioactive lipids, with deleterious consequences affecting both neurons and glial cells favoring disease progression.

Fatty acids are key components in the structural diversity of lipids and play a strategic role in the functional properties of lipids which determine the integrity of neuronal and glial cell membranes, the generation of lipid signaling mediators, and the chemical reactivity of acyl chains. The present study analyzes using gas chromatography the fatty acid profiles of 13 regions of the human central nervous system in healthy individuals ranging from 40 to 80 years old. The outcomes suggest the existence of general traits in fatty acid composition such as an average chain length of 18 carbon atoms, high monounsaturated fatty acid content, and predominance in polyunsaturated fatty acids of those of series n-6 over series n-3 which are shared by all brain regions regardless of age. Our results also show a general sustained and relatively well-preserved lipid profile throughout the adult lifespan in most studied regions (olive, upper vermis, substantia nigra, thalamus, hippocampus, putamen, caudate, occipital cortex, parietal cortex, entorhinal cortex, and frontal cortex) with minor changes that are region-dependent. In contrast, of particular relevance is the involvement of the inferior temporal cortex and cingulate cortex. It is proposed that during normal human brain aging, the lipid profile is resistant to changes with age in most human brain regions to ensure cell survival and function, but some particular regions involved in specific memory domains are greatly affected. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was funded by the Spanish Ministry of Science, Innovation, and Universities (grant RTI2018-099200-B-I00), the IRBLleida-Dipuatació de Lleida (PIRS2021), and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696) to R.P. This study was cofnanced by FEDER funds from the European Union (“A way to build Europe”). IRBLleida is a CERCA Programme/Generalitat of Catalonia.

Transient ischemic attacks (TIAs) before an acute ischemic stroke (AIS) could induce ischemic tolerance (IT) phenomena. with an endogenous neuroprotective role (Ischemic preconditioning. IPC). A consecutive prospective cohort of patients with AIS were recruited from 8 different hospitals. Participants were classified by those with non-previous recent TIA vs. previous TIA (within seven days. TIA ≤7d). A total of 541 AIS patients were recruited. 40 (7.4%). of them had previous TIA ≤7d. In line with IPC. patients with TIA ≤7d showed: 1) a significantly less severe stroke at admission by NIHSS score. 2) a better outcome at 7–90 days follow-up and reduced infarct volumes. 3) a specific upregulated metabolomics/lipidomic profile composed of diverse lipid categories. Effectively. IPC activates an additional adaptive response on increasing circulation levels of structural and bioactive lipids to facilitate functional recovery after AIS which may support biochemical machinery for neuronal survival. Furthermore. previous TIA before AIS seems to facilitate the production of anti-inflammatory mediators that contribute to a better immune response. Thus. the IT phenomena contributes to a better adaptation of further ischemia. Our study provides first-time evidence of a metabolomics/lipidomic signature related to the development of stroke tolerance in AIS patients induced by recent TIA.

Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD., Regional Government of Andalusia, Excellence Research (Project No P12-AGR-2581), Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00), Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696), Department of Health (SLT002/16/00250), FEDER - European Union (“A way to build Europe”)., IRBLleida - CERCA Programme/Generalitat of Catalonia, “Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid

Available evidences point to methionine metabolism as a key target to study the molecular adaptive mechanisms underlying differences in longevity. The plasma methionine metabolic profile was determined using a LC-MS/MS platform to systematically define specific phenotypic patterns associated with genotypes of human extreme longevity (centenarians). Our findings demonstrate the presence of a specific plasma profile associated with human longevity characterized by an enhanced transsulfuration pathway and tricarboxylic acid (TCA) cycle intermediates, as well as a reduced content of specific amino acids. Furthermore, our work reveals that centenarians maintain a strongly correlated methionine metabolism, suggesting an improved network integrity, homeostasis and more tightly regulated metabolism. We have discovered a particular methionine signature related to the condition of extreme longevity, allowing the identification of potential mechanisms and biomarkers of healthy aging.

Lipids are closely associated with brain structure and function. However, the potential changes in the lipidome induced by aging remain to be elucidated. In this study, we used chromatographic techniques and a mass spectrometry-based approach to evaluate age-associated changes in the lipidome of the frontal cortex and cerebellum obtained from adult male Wistar rats (8 months), aged male Wistar rats (26 months), and aged male Wistar rats submitted to a methionine restriction diet (MetR) as an anti-aging intervention for 8 weeks. The outcomes revealed that only small changes (about 10%) were observed in the lipidome profile in the cerebellum and frontal cortex during aging, and these changes differed, in some cases, between regions. Furthermore, a MetR diet partially reversed the effects of the aging process. Remarkably, the most affected lipid classes were ether-triacylglycerols, diacylglycerols, phosphatidylethanolamine N-methylated, plasmalogens, ceramides, and cholesterol esters. When the fatty acid profile was analyzed, we observed that the frontal cortex is highly preserved during aging and maintained under MetR, whereas in the cerebellum minor changes (increased monounsaturated and decreased polyunsaturated contents) were observed and not reversed by MetR. We conclude that the rat cerebellum and frontal cortex have efficient mechanisms to preserve the lipid profile of their cell membranes throughout their adult lifespan in order to maintain brain structure and function. A part of the small changes that take place during aging can be reversed with a MetR diet applied in old age. This research was funded by the Spanish Ministry of Science, Innovation, and Universities (grant RTI2018-099200-B-I00), and the Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696) to R.P.; and from Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI20-0155) to M.P.-O. This study was co-financed by FEDER funds from the European Union (“A way to build Europe”). IRBLleida is a CERCA Programme/Generalitat of Catalonia.