Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer’s disease: a tale of shotgun lipidomics
Xianlin Han
Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Address correspondence and reprint requests to Xianlin Han, Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St Louis, MO 63110, USA, E-mail: xianlin@wustl.edu

AbstractShotgun 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.
Keywords: Alzheimer’s disease, apolipoprotein E, electrospray ionization, lipidomics, mass spectrometry, shotgun lipidomics, sulfatide metabolism



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N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology
John R. Moffett,1,2 Brian Ross,3 Peethambaran Arun,1 Chikkathur N. Madhavarao,1 and M. A. A. Namboodiri1
1 Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Building C, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA
3 Magnetic Resonance Unit, Huntington Medical Research Institutes, Pasadena, CA; Rudi Schulte Research Institute, Santa Barbara CA and NARSAD
2 Contact: J.R. Moffett, phone (301) 295-9357, fax (301) 295-3566, Email: jmoffett@usuhs.mil.

AbstractThe brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.
Keywords: NAA, Canavan disease, myelination, dysmyelination, lipid synthesis, aspartoacylase, energy metabolism, N-acetyl-L-aspartic acid, acetate, acetyl coenzyme A



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Plasticity in the Olfactory System: Lessons for the Neurobiology of Memory
D. A. WILSON, A. R. BEST, and R. M. SULLIVAN
Department of Zoology, University of Oklahoma
Address correspondence to: Donald A. Wilson, Department of Zoology, University of Oklahoma, Norman, OK 73019 (e-mail: dwilson@ou.edu).


AbstractWe are rapidly advancing toward an understanding of the molecular events underlying odor transduction, mechanisms of spatiotemporal central odor processing, and neural correlates of olfactory perception and cognition. A thread running through each of these broad components that define olfaction appears to be their dynamic nature. How odors are processed, at both the behavioral and neural level, is heavily dependent on past experience, current environmental context, and internal state. The neural plasticity that allows this dynamic processing is expressed nearly ubiquitously in the olfactory pathway, from olfactory receptor neurons to the higher-order cortex, and includes mechanisms ranging from changes in membrane excitability to changes in synaptic efficacy to neurogenesis and apoptosis. This review will describe recent findings regarding plasticity in the mammalian olfactory system that are believed to have general relevance for understanding the neurobiology of memory.
Keywords: Olfaction, Plasticity, Memory, Learning, Perception

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