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A Signaling Lipid Associated with Alzheimer’s Disease Promotes Mitochondrial Dysfunction

ABSTRACT: Fundamental changes in the composition and distribution of lipids within the brain are believed to contribute to the cognitive decline associated with Alzheimer’s disease (AD). The mechanisms by which these changes in lipid composition affect cellular function and ultimately cognition are not well understood. Although “candidate gene” approaches can provide insight into the effects of dysregulated lipid metabolism they require a preexisting understanding of the molecular targets of individual lipid species. In this report we combine unbiased gene expression profiling with a genomewide chemogenomic screen to identify the mitochondria as an important downstream target of PC(O-16:0/2:0), a neurotoxic lipid species elevated in AD. Further examination revealed that PC(O-16:0/2:0) similarly promotes a global increase in ceramide accumulation in human neurons which was associated with mitochondrial-derived reactive oxygen species (ROS) and toxicity. These findings suggest that PC(O-16:0/2:0)-dependent mitochondrial dysfunction may be an underlying contributing factor to the ROS production associated with AD.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE40814 | GEO | 2016/01/21

SECONDARY ACCESSION(S): PRJNA175033

REPOSITORIES: GEO

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Project description:Pseudoexfoliation syndrome (PEX) is systemic disorder that manifests as white, fluffy, proteinaceous fibrillar material throughout the body. In the eye such deposits result in Pseudoexfoliation glaucoma (PEXG), due to impeding aqueous humor outflow. Serum lipid alterations and increased lipid peroxidation have been reported in PEX. We report first ever comprehensive lipid profiling of the aqueous humor (AH) of PEXG. Our untargeted lipidomic analysis of 23 non-glaucomatous control, 19 primary open angle glaucoma, 9 PEX, and 14 PEXG AH with 13 deuterated lipid internal standards for normalization among the lipid classes resulted in the combined identification of 489 lipid species within 26 lipid classes across PEX, PEXG, POAG, and control AH. The mean total lipid content in the AH across samples showed that control AH (mean peak area 13.54 ± 56.1) had, on average, greater total lipid content than PEX (4.21 ± 10.90), PEXG (9.08 ± 25.97), and POAG (5.66 ± 15.75) samples. Multiple cholesterol esters (ChE), phosphatidylcholines (PC), triglycerides (TG), and ceramides (Cer) were present in higher concentrations for the PEXG AH samples. Some of the lipids found in high concentrations in the PEXG samples are ChE(16:0), ChE(20:3), ChE(18:1), ChE(18:3), ChE(22:6), ChE(18:2), ChE(20:4), PC(16:0/16:0), PC(16:0/18:2), TG(18:1/18:1/20:4), and Cer(t18:0/24:0). The CerG2GNAc1(d34:1) was enriched in control samples and depleted both in PEX and PEXG samples. The PC (18:0/18:2), PC (36:2), and PC (34:1e) are in low concentrations for PEX but highly concentrated in PEXG, despite both having similar material deposits, suggesting they are fundamentally different in composition. Elevations in Apolipoprotein A-I (APOA1) correlated to increase abundance of PC lipid species in the AH of patients with PEXG. Machine learning prediction with three supervised logistic regression binary classification tasks showed 1) POAG vs control, with 86% accuracy 2) PEXG vs control, with 71% accuracy and 3) PEX vs control, with 86% accuracy, respectively.

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A Signaling Lipid Associated with Alzheimer’s Disease Promotes Mitochondrial Dysfunction

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