Investigation of the Sphingolipid pathway in the early stages of Alzheimer's disease

Download files
Access & Terms of Use
open access
Copyright: Kain, Nupur
Altmetric
Abstract
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease and a significant burden on families and society. A major hallmark of AD is lipid occlusions within neural cell types, indicating dysfunctional lipid metabolism. Sphingolipids (SL), a subgroup of lipids, play a vast array of functions in the CNS, including as essential components of myelin, a hydrophobic barrier insulating axons and facilitating action potential propagation. SL dysregulation has been studied in post mortem AD affected brain tissues compared to controls, however, SL changes in pre-clinical stages of AD has not been investigated. Applying liquid chromatography tandem mass spectrometry, this thesis describes the sphingolipid profile of six AD affected brain regions infiltrated to varying degrees by neurofibrillary tangle (NFT) pathology, indicated by Braak staging I-VI. A pronounced loss in myelin lipids galactosylceramide (GalCer) and sulfatide from frontal and temporal grey matter (GM) and hippocampus was observed, leading to investigation of de novo synthesis of the precursor ceramide. Activity of the enzyme ceramide synthase 2 (CERS2), essential for very long chain ceramide synthesis and myelin lipid production, was significantly reduced in multiple brain regions at a stage of disease preceding characteristic NFT pathology. Lipid analysis also showed a marked decline of the neuroprotective signalling lipid sphingosine 1-phosphate (S1P) in hippocampus and temporal GM that tracked closely with NFT pathology. S1P loss was attributed to loss of activity in sphingosine kinases 1 and 2, required for S1P synthesis. The major genetic risk factor of AD is expression of the E4 isoform of the apolipoprotein E (ApoE) lipid transporter, which aids in brain lipid delivery and clearance. Despite no correlation between APOE genotype and ceramide levels, a positive correlation between age and C16 ceramide, recently associated with systemic insulin resistance, was observed. Overall we hypothesise that CERS2 activity loss destabilises myelin, triggering neurological decline and sensitising neurons to AD induced neurotoxicity. The effect of insulin resistance in the AD affected brain including cognitive function is garnering interest in AD research, warranting further investigation into the study of C16 ceramide levels with age. Pharmacological restoration of deficient S1P signalling could also open therapeutic perspectives for AD.
Persistent link to this record
Link to Publisher Version
Link to Open Access Version
Additional Link
Author(s)
Kain, Nupur
Supervisor(s)
Don, Anthony
Creator(s)
Editor(s)
Translator(s)
Curator(s)
Designer(s)
Arranger(s)
Composer(s)
Recordist(s)
Conference Proceedings Editor(s)
Other Contributor(s)
Corporate/Industry Contributor(s)
Publication Year
2016
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
Files
download public version.pdf 5.66 MB Adobe Portable Document Format
Related dataset(s)