The cholesterol-ceramide connection as a possible link between The cholesterol-ceramide connection as a possible link between diabetes and Alzheimer’s disease   Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, PERTH, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Sir James McCusker Alzheimer's Disease Research Foundation, Hollywood Private Hospital, Perth, WA. I.J.Martins, R.Creegan, W.L.F Lim, V. Gupta, S. Guanghou and R.N.Martins INTRODUCTION Molecular mechanisms involved with neuroendocrine diseases such as obesity and diabetes are closely linked to insulin resistance and require attention since metabolic dysfunction has also been associated with neurodegeneration. The global increase in these chronic diseases support a role for lipids such as cholesterol, sphingomyelin (SM) and its metabolites in the pathogenesis of these diseases. The cholesterol-ceramide connection has been previously linked with aging and Alzheimer’s disease (AD). Lipidomics as a tool for development with diagnosis of abnormal lipid metabolism as an early lipid biomarker panel has become important to diabetes and AD since its comparison and inclusion with other biomarker panels will allow sensitive detection and early diagnosis of metabolic dysfunction and its relevance to AD. Lipids such as cholesterol and ceramide (CER) have been linked to insulin resistance with connections to processing of the amyloid precursor protein (APP) and generation or regulation of beta- amyloid production that is central to the amyloid hypothesis in AD. METHODS Lipidomic analysis using mass spectrometry of fasting plasma from an ageing cohort (AIBL) cognitively healthy controls and AD patients with apo E4 allele status at baseline have been provided in this study. Lipids extracted using a modified Bligh Dyer method (chloroform/methanol) and spiked with appropriate amounts of internal standard cocktail. Analysis performed on ABSciex 4000 QTRAP mass spectrometer via direct flow injection with an ESI source(REF1).Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylinositol (PI), Phosphatidylglycerol (PG) The AD group may be a complex group of individuals and the lipidomic biomarker panel will allow important differences to be shown in genuine AD patients for early diagnosis of abnormal peripheral amyloid beta homeostasis with relevance to diabetes and AD. The plasma lipid ceramide level was significantly increased and phospholipid lipid transfer activity (PLTP) were decreased in AD patients. Sphingomyelin levels were found to be markedly decreased in the AD group. Other plasma phospholipids were also altered with plasma lipid increases and decreases in these AD individuals when compared with healthy controls (TABLE 1). The low sphingomyelin species, elevated ceramide species and decreased PLTP plasma activity indicate increased oxidative stress associated with abnormal peripheral amyloid beta homeostasis with relevance to diabetes and AD. REF 1.Plasma lipidomics in Alzheimer’s disease. The Australian Imaging, Biomarkers and lifestyle study of ageing. R.Creegan et al. Poster Session. The 11th International conference on Alzheimer’s and Parkinson’s diseases. AD/PD 2013. Florence, ITALY. www.kenes.com.adpd. NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL OF AUSTRALIA Figure 1. Effects of insulin resistance on PLTP, hepatic ceramide lipoprotein secretion and on ceramide APP-Abeta processing. In AD patients the increased ceramide and lower sphingomyelin levels are possibly associated with abnormal plasma lipoprotein lipid content with relevance to abnormal cholesterol transport in diabetes and AD. REF 2 and REF 3 RESULTS Figure 2. Effects of abnormal sphingomyelin and cholesterol interactions on cell and nuclear membranes that control cell function and amyloid beta metabolism in diabetes and AD. REF 2 and REF 3 CONCLUSIONS 1. Plasma sphingomyelin, ceramide and phospholipids are closely linked to insulin resistance and require attention with the global increase in chronic diseases that support a role for lipids such as cholesterol, sphingomyelin and its metabolites in the pathogenesis of diseases such as diabetes and AD. 2. Lipidomics as a tool for development with diagnosis of abnormal lipid metabolism as an early lipid biomarker panel has become important to diabetes and Alzheimer’s disease since high plasma ceramide levels linked to insulin resistance are also involved in the processing of APP and beta-amyloid production that is central to the amyloid hypothesis in AD. 3. Diets that lower ceramide levels may be involved in the reversal of chronic diseases such as diabetes, NAFLD, stroke and AD in Western populations. FUTURE STUDIES may involve lipidomic assessment of cell nuclear lipid profiles with relevance to early apoptosis when compared with plasma sphingomyelin and ceramide levels with relevance to harness novel therapy for diabetes and neurodegeneration. REFERENCES: REF 2 Martins, IJ and Creegan, R. (2014) Links between Insulin Resistance, Lipoprotein Metabolism and Amyloidosis in Alzheimer’s Disease. Health, 6, 1549-15793. REF 3 WLF Lim, IJ Martins and RN Martins The Involvement of Lipids in Alzheimer's Disease, Lipid Metabolism and Lipidomics: An Emerging Frontier in Biology Journal of Genetics and Genomics 41, 5, 2014, 261–274 Annual World Congress of Diabetes 2014 (WCD-2014) “The Present Situation and Outlook in Diabetes”