Klein, J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J. Neural Transm. 107, 1027-1063

Department of Pharmacology, University of Mainz, Federal Republic of Germany.
Journal of Neural Transmission (Impact Factor: 2.4). 02/2000; 107(8-9):1027-63. DOI: 10.1007/s007020070051
Source: PubMed


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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    • "Muscarinic M1 receptors activated by pilocarpine mobilize intracellular calcium, and the glutamatergic NMDA receptor channel is a calcium-permeable ion channel. Release of isoprostanes, and breakdown of phospholipids to yield glycerol and choline, are likely catalyzed by calciumdependent isoforms of phospholipase A 2 (Klein 2000; Burke and Dennis 2009). Moreover, one previous study gave evidence that SE is accompanied by a persistent elevation of intracellular calcium in hippocampal neurons in vitro (Pal et al. 1999). "
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    ABSTRACT: The lithium-pilocarpine model of status epilepticus is a well-known animal model of temporal lobe epilepsy. We combined this model with in vivo-microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). 24 hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase of glucose and a prominent, five-fold increase of lactate during seizures. Lactate release was due to neuronal activation because it was strongly reduced by infusion of tetrodotoxin, administration of atropine, or when seizures were terminated by diazepam or ketamine. In ex vivo-assays, mitochondrial function as measured by respirometry was not affected by 90 minutes of seizures. Extracellular levels of choline, however, increased twofold, and glycerol levels ten-fold, which indicates cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold, and formation of isoprostanes twenty-fold, revealing significant oxidative stress in hippocampal tissue. Increases of lactate, glycerol and isoprostanes were abrogated, and increases of choline completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases of extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains normal for at least 90 minutes. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 09/2015; DOI:10.1111/jnc.13360 · 4.28 Impact Factor
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    • "The Cho signal is mainly due to the presence of free glycerophosphocholine and phosphocholine. These compounds are immobile when part of the cellular membrane, but they become mobile and contribute to the Cho signal when the cell membrane has broken down [19]. There are publications reporting an increase of Cho in AD subjects [20] [21]. "
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    ABSTRACT: Background: The application of non-invasive proton magnetic resonance spectroscopy (1H-MRS) could potentially identify changes in cerebral metabolites in the patients with Alzheimer's disease (AD). However, whether these metabolites can serve as biomarkers for the diagnosis of AD remains unclear. Objective: Using meta-analysis, we aimed to investigate the patterns of cerebral metabolite changes in several cerebral regions that are strongly associated with cognitive decline in AD patients. Methods: Using Hedges' g effect size, a systematic search was performed in PubMed, Cochrane Library, Ovid, Embase, and EBSCO, and 38 studies were integrated into the final meta-analysis. Results: According to the observational studies, N-acetyl aspartate (NAA) in AD patients was significantly reduced in the posterior cingulate (PC) (effect size (ES) = -0.924, p<0.005) and bilateral hippocampus (left hippocampus: ES = -1.329, p<0.005; right hippocampus: ES = -1.287, p<0.005). NAA/Cr (creatine) ratio decreased markedly in the PC (ES = -1.052, p<0.005). Simultaneously, significant elevated myo-inositol (mI)/Cr ratio was found not only in the PC but also in the parietal gray matter. For lack of sufficient data, we failed to elucidate the efficacy of pharmacological interventions with the metabolites changes. Conclusion: The available data indicates that NAA, mI, and the NAA/Cr ratio might be potential biomarkers of brain dysfunction in AD subjects. Choline (Cho)/Cr and mI/NAA changes might also contribute toward the diagnostic process. Thus, large, well-designed studies correlated with cerebral metabolism are needed to better estimate the cerebral extent of alterations in brain metabolite levels in AD patients.
    Journal of Alzheimer's disease: JAD 06/2015; 46(4):1049-1070. DOI:10.3233/JAD-143225 · 4.15 Impact Factor
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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 · 6.34 Impact Factor
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