Membrane breakdown in acute and chronic neurodegeneration: Focus on choline-containing phospholipids

Department of Pharmacology, University of Mainz, Federal Republic of Germany.
Journal of Neural Transmission (Impact Factor: 2.87). 02/2000; 107(8-9):1027-63. DOI: 10.1007/s007020070051
Source: PubMed

ABSTRACT Breakdown of cellular membranes is a characteristic feature of neuronal degeneration in acute (stroke) and chronic (senile dementia) neurological disorders. The present review summarizes recent experimental and clinical work which concentrated on changes of choline-containing phospholipids as indicators of neuronal membrane breakdown. Experimental studies identified glutamate release, calcium influx, and activation of cellular phospholipase A2 (PLA2) as important steps initiating membrane breakdown in cultured neurons or brain slices under hypoxic or ischemic conditions. Proton NMR studies have shown an elevation of choline-containing compounds in the brain of Alzheimer patients while neurochemical studies in post mortem-brain demonstrated increases of the catabolic metabolite, glycerophosphocholine, an indicator of PLA2 activation. In contrast, studies of cerebrospinal fluid, phosphorus NMR studies, and measurements of phospholipases in post mortem Alzheimer brain gave ambiguous results which may be explained by methodical limitations. The finding that, in experimental studies, choline was a rate-limiting factor for phospholipid biosynthesis has stimulated clinical studies aimed at counteracting phospholipid breakdown, e.g. by combinations of choline and cytidine. Future experimental approaches should clarify whether loss of membrane phospholipids is cause or consequence of the neurodegenerative disease process.

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    • "The Cho/Cr metabolite ratio is thought to represent membrane turnover, as the choline peak is considered to be the breakdown products of phosphatidylcholine – one of the principle components of the cell membrane's phospholipid bilayer (Klein, 2000). Changes in the Cho/Cr ratio in AD dementia have inconsistently been reported to be elevated (Pfefferbaum et al., 1999; Kantarci et al., 2004) or show no change (Moats et al., 1994; Schuff et al., 1997; Rose et al., 1999; Krishnan et al., 2003). "
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    ABSTRACT: Proton magnetic resonance spectroscopy ((1)H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although (1)H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the (1)H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem (1)H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. (1)H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD. Copyright © 2014 the authors 0270-6474/14/3416247-09$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2014; 34(49):16247-55. DOI:10.1523/JNEUROSCI.2027-14.2014 · 6.75 Impact Factor
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    • "However, neuronal trauma and neurodegenerative diseases can stimulate phospholipase activity and result in changes in phospholipid composition. One of the key pathological events during neurodegeneration is excitotoxicity, i.e., toxicity as a result of overstimulation of neurons by the excitatory neurotransmitter, glutamate (Klein, 2000). The postulated sequence of events in hypoxia suggests a reduction in ATP levels due to loss of energy production , followed by glutamate release, and excessive stimulation of glutamate receptors causing an influx of calcium (Rothman & Olney, 1995). "
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    ABSTRACT: Choline is an essential nutrient and an integral component of several fundamental neurochemical processes. This chapter will provide an overview of the biochemistry of choline, its biosynthetic pathways, role as a dietary nutrient, and involvement in phospholipid metabolism. Metabolic changes that occur in conditions affecting the biosynthesis of phospholipids and cellular membrane integrity (e.g., neoplasms and neurological disorders) are discussed within the context of magnetic resonance spectroscopy.
    Magnetic Resonance Spectroscopy: Tools for Neuroscience Research and Emerging Clinical Applications, 1 edited by C. J. Stagg, D. L. Rothman, 12/2013: chapter 2.3: pages 104-110; Academic Press., ISBN: 978-0-12-401688-0
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    • "Here, we seek to identify some of these additional critical disruptions by mining existing neurolipidomic datasets. Previous work has correlated the extent of membrane phosphocholine (PC) and phosphoethanolamine (PE) breakdown with severity of dementia and psychosis in AD patients (Klein, 2000; Sweet et al., 2002). Moreover, soluble oligomeric Aβ 42 neurotoxicity is signaled, in part, by enhanced metabolism of ether linked structural phospholipids (Sanchez- Mejia et al., 2008; Ryan et al., 2009). "
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    ABSTRACT: Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.
    Frontiers in Physiology 07/2013; 4:168. DOI:10.3389/fphys.2013.00168 · 3.50 Impact Factor
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