Excitotoxic mechanisms in the pathogenesis of dementia

Dodd, Peter R.; Scott, H. L.; Westphalen, Robert I.

doi:10.1016/0197-0186(94)90064-7

Cited by 53 publications

(26 citation statements)

References 127 publications

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“…Excessive activation of such cells in various pathologic conditions is likely to cause an export of large fraction of intramitochondrial acetyl-CoA to cytoplasm for ACh synthesis, thereby decreasing the amount of this intermediate available for energy production. Such a situation could take place in brain in vivo during ischemia or during excessive activation of NMDA receptors (Dodd et al, 1994;Blass, 1996).…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line

et al. 1999

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The rate of acetylcholine (ACh) synthesis was found to depend on the activity of choline acetyltransferase (ChAT) and on the concentrations of the two substrates of this enzyme, choline and acetyl-CoA. In SN56 cells treated for 3 days with 1 mM dbcAMP activities of ChAT and acetylcholinesterase (AChE) were elevated. It was accompanied by an increased activity of ATP-citrate lyase (ACL)-an enzyme responsible for provision of part of acetyl-CoA for ACh synthesis in cholinergic neurons. In contrast lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) activities were reduced by dbcAMP. Treatment with 0.001 mM all-trans retinoic acid (RA) elevated ChAT and LDH activities but reduced the activities of AChE and ACL. The combined treatment with db-cAMP and tRA increased ChAT activity in supra-additive fashion. The effects of these two compounds on the other enzymes were not additive. Neither compound altered the activities of carnitine acetyl-transferase, acetyl-CoA synthase, or acetyl-CoA hydrolase. On the other hand, they decreased acetyl-CoA content and rate of ACh release. Overall, the results indicate that tRA upregulates only ChAT expression, whereas dbcAMP upregulates several features of cholinergic neurons including ChAT, AChE, and ACL. Low levels of acetyl-CoA in differentiated cells may result in a low rate of ACh release and resynthesis during their depolarization.

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Section: Discussionmentioning

confidence: 99%

Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line

et al. 1999

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“…Altered glutamate transport has been implicated in Alzheimer's disease (AD), with biochemical studies showing reduced numbers of high-affinity glutamate uptake sites in AD in many cortical areas and a lower maximal D-[ 3 H]aspartate uptake rate (early studies by Cross et al, 1987;Cowburn et al, 1988) (for review, see Scott et al, 1995). Different pharmacological profiles of glutamate transporter sites have also been found in a number of cortical regions in AD cases compared with controls (Dodd et al, 1994).…”

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confidence: 99%

Aberrant Expression of the Glutamate Transporter Excitatory Amino Acid Transporter 1 (EAAT1) in Alzheimer's Disease

Scott¹,

Pow²,

Tannenberg³

et al. 2002

J. Neurosci.

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111

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Glutamate-mediated toxicity has been implicated in the neurodegeneration observed in Alzheimer's disease. In particular, glutamate transport dysfunction may increase susceptibility to glutamate toxicity, thereby contributing to neuronal cell injury and death. In this study, we examined the cellular localization of the glial glutamate transporter excitatory amino acid transporter 1 (EAAT1) in the cerebral cortex of control, Alzheimer's disease, and non-Alzheimer dementia cases. We found that EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology.In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1. These findings suggest that EAAT1 changes are related to tau expression (and hence neurofibrillary tangle formation) in dementia cases showing Alzheimer-type pathology. This study implicates aberrant glutamate transporter expression as a mechanism involved in neurodegeneration in Alzheimer's disease.

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“…EXCITATORY amino acids have been implicated as important mediators in the process of neuronal cell death in hypoxia, ischaemia and chronic neurodegenerative diseases (Choi et al, 1995;Coyle & Puttfarken, 1993;Dodd et al, 1994;Maragos et al, 1987;Rothman & Olney, 1986). During cerebral ischaemia excessive release of the excitatory neurotransmitter glutamate is observed (Benveniste et al, 1984), which leads to an uncontrolled rise of intracellular free Ca 2ϩ (Dubinsky, 1993) and ultimately to neuronal necrosis (Randall & Thayer, 1992).…”

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confidence: 99%

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

et al. 1996

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Excitotoxic mechanisms in the pathogenesis of dementia

Cited by 53 publications

References 127 publications

Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line

Acetylcholine and acetyl-CoA metabolism in differentiating SN56 septal cell line

Aberrant Expression of the Glutamate Transporter Excitatory Amino Acid Transporter 1 (EAAT1) in Alzheimer's Disease

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

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