title: Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer's disease.
abstract: The anatomical progression of neurofibrillary tangle pathology throughout Alzheimer's disease (AD) pathogenesis runs inverse to the pattern of developmental myelination, with the disease preferentially affecting thinly myelinated regions. Myelin is comprised 80% of lipids, and the prototypical myelin lipids, galactosylceramide, and sulfatide are critical for neurological function. We observed severe depletion of galactosylceramide and sulfatide in AD brain tissue, which can be traced metabolically to the loss of their biosynthetic precursor, very long chain ceramide. The synthesis of very long chain ceramides is catalyzed by ceramide synthase 2 (CERS2). We demonstrate a significant reduction in CERS2 activity as early as Braak stage I/II in temporal cortex, and Braak stage III/IV in hippocampus and frontal cortex, indicating that loss of myelin-specific ceramide synthase activity precedes neurofibrillary tangle pathology in cortical regions. These findings open a new vista on AD pathogenesis by demonstrating a defect in myelin lipid biosynthesis at the preclinical stages of the disease. We posit that, over time, this defect contributes significantly to myelin deterioration, synaptic dysfunction, and neurological decline.
authors.affiliation: Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Couttas
authors.affiliation: Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Nupur
authors.initials: N
authors.lastname: Kain
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Suchowerska
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Lake-Ee
authors.initials: LE
authors.lastname: Quek
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fath
authors.affiliation: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
authors.affiliation: Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. Electronic address: anthonyd@unsw.edu.au.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism*; D051049:Sphingosine N-Acyltransferase / Q000172:deficiency*; D024801:Tauopathies / Q000209:etiology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D016875:tau Proteins; C438311:CERS2 protein, human; D051049:Sphingosine N-Acyltransferase
keywords: Alzheimer's disease; Ceramide; Ceramide synthase 2; Galactosylceramide; Myelin; Sulfatide