Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer's disease: a tale of shotgun lipidomics.

Shotgun lipidomics is a rapidly developing technology, which identifies and quantifies individual lipid molecular species directly from lipid extracts of biological samples. Alterations in lipid molecular species in the brain induced by neurodegenerative diseases, such as Alzheimer's disease (AD) could provide fundamental clues to disease pathogenesis. To date, the cause(s) leading to AD pathogenesis are still unknown and apolipoprotein E (apoE) allele 4 is the only known major risk factor for this devastating disease. By utilizing shotgun lipidomics, we have recently shown that a substantial and specific depletion of sulfatide (a class of specialized myelin sphingolipids) is present in postmortem brains from subjects at the earliest clinically recognizable stage of AD. In subsequent studies to identify the biochemical mechanisms underlying sulfatide depletion at this very mild stage of AD, we have found that apoE is associated with sulfatide transport and mediates sulfatide homeostasis in the nervous system through lipoprotein metabolism pathways and that alterations in apoE-mediated sulfatide trafficking can lead to sulfatide depletion in the brain. Thus, a working model related to the potential biochemical mechanisms underlying sulfatide depletion in AD can be derived based on these results. Collectively, the results obtained from lipidomic analyses of brain samples provide important insights into the biochemical mechanisms underlying AD pathogenesis.