Sol, J. | Search bioRxiv

bioRxiv2022

Lipidomic alterations in the cerebral cortex and white matter in sporadic Alzheimer's disease

AimsNon-targeted lipidomics analysis was conducted in post-mortem human frontal cortex area 8 (GM) and white matter of the frontal lobe centrum semi-ovale (WM) to identify lipidomes in middle-aged individuals with no neurofibrillary tangles and senile plaques, and cases at progressive stages of sporadic Alzheimers 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.

neuroscience↗

bioRxiv2019

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines-including plasmalogens- and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in related-enzymes, such as phospholipase C {beta}I (PLC{beta}I), the source of nuclear diacylglycerol, and protein kinase C{beta}II (PKC{beta}II), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

neuroscience↗