The association of [3H]d-aspartate binding and high-affinity glutamate uptake in the human brain

Cross, A.J.; Skan, Wendy; Slater, P.

doi:10.1016/0304-3940(86)90047-9

Cited by 44 publications

(14 citation statements)

References 13 publications

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“…2A) confirms and extends previous findings based largely on homogenate preparations (13-15). DAspartate is a substrate for the high-affinity glutamate uptake system (35) and has been proposed to be a suitable marker of glutamate-releasing nerve terminals in human brain (36). The present data, therefore, indicate a marked loss of glutamatergic terminals in SDAT frontal cortex.…”

Section: Discussionmentioning

confidence: 48%

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Chalmers

Dewar

Graham

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Involvement of cortical glutamatergic mechanisms in senile dementia of the Alzheimer type (SDAT) has been investigated with quantitative ligand-binding autoradiography. The distribution and density of Na+-dependent glutamate uptake sites and glutamate receptor subtypes-kainate, quisqualate, and N-methyl-D-aspartate-were measured in adjacent sections of frontal cortex obtained postmortem from six patients with SDAT and six age-matched controls. The number of senile plaques was determined in the same brain region. [3H]Glutamate binding in SDAT subjects was unrelated to senile plaque number in superficial cortical layers (r = 0.104). These results indicate that in the presence of cortical glutamatergic terminal loss in SDAT plastic alterations occur in some glutamate receptor subtypes but not in others.Senile dementia of the Alzheimer type (SDAT) is characterized neuropathologically by neuronal cell loss, the presence of higher than normal densities of senile plaques, and the development of neurofibrillary tangles in neocortical and archicortical regions (1-3). Extensive neurochemical studies have indicated deficits in a number of neurotransmitters and neurotransmitter receptors in SDAT cerebral cortex (4-7). The relationship of these changes to the neuropathological progression of the disease, however, remains largely unknown.Glutamate is putatively the major excitatory transmitter of cortical pyramidal neurons (8), which mediate corticocortical and corticofugal neurotransmission (9). A loss of cortical pyramidal cells is a prominent feature of SDAT pathology (2, 3, 10); thus, cortical glutamatergic dysfunction may be a contributory factor in the pathophysiological progression of the disease. In rodents, glutamate receptormediated excitotoxicity in the cerebral cortex induces retrograde degeneration of cholinergic neurons in the nucleus basalis (11), supporting the suggestion that cortical cholinergic axon degeneration in SDAT may be a consequence of a primary cortical pathology (12 (14,15,(17)(18)(19)(20).Using quantitative ligand-binding autoradiography, we have measured the distribution and density of both highaffinity Na+-dependent glutamate-uptake sites and the three glutamate receptor subtypes in adjacent sections of frontal cortex from SDAT patients and age-matched controls. These neuropharmacological measures could be directly related to the neuropathological severity of the disease by quantification of senile plaque numbers in the same brain region. MATERIALS AND METHODSBrains were obtained at postmortem from six subjects, mean age 84 ± 2 yr, who had no known neurological or neuropsychiatric disorders (two males, four females; postmortem delay 11-23 hr), and six clinically diagnosed SDAT patients, mean age 89 ± 2 yr (two males, four females; postmortem delay 3-15 hr). As part of an ongoing longitudinal study of SDAT, these patients were diagnosed antemortem according to the criteria set out in the Cambridge Diagnostic Examination for the Elderly (21). Eight of the twelve patients used in this stud...

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Section: Discussionmentioning

confidence: 48%

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Chalmers

Dewar

Graham

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…3 H]aspartate (NEN Life Science Products) to membrane preparations from neocortex was determined by a method modified from Cross et al (43) and used to estimate neocortical glutamate/aspartate uptake, essentially as described previously (44). Before analysis, all samples were assigned codes, and the codes were broken only after all results had been downloaded into the data base.…”

Section: Aspartate Binding and Aspartate Uptake Assays-binding Of D-[mentioning

confidence: 99%

Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport

Masliah¹,

Raber²,

Alford³

et al. 1998

Journal of Biological Chemistry

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Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

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“…Indeed, the amounts of binding observed were substantially greater than reported for previous methods involving filtration separation techniques (Cross et al, 1986). Indeed, the amounts of binding observed were substantially greater than reported for previous methods involving filtration separation techniques (Cross et al, 1986).…”

Section: Discussionmentioning

confidence: 54%

D-aspartate binding to the glutamate uptake site in human brain tissue ? effects of leucotomy

Cutts

Reynolds

1993

J. Neural Transmission

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Binding of [3H]D-aspartate, as an indicator of glutamate uptake sites, was investigated in post-mortem human brain tissue by use of a centrifugation assay to separate free and bound ligand. Binding was displaceable, apparently saturable and to a single site, with mean KD and Bmax values of 2.3 microM and 40.3 nmol/g tissue in the frontal cortex. The method was applied to the study of tissue from frontal and temporal cortices and the caudate nucleus of five psychiatric patients who had undergone a frontal leucotomy. The effects of this neurosurgical procedure were to diminish by almost 50% the density of D-aspartate binding sites in the frontal cortex and caudate nucleus, while the temporal cortex was less affected. It is concluded that the method provides a potentially useful correlate of glutamatergic innervation in human brain tissue.

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The association of [3H]d-aspartate binding and high-affinity glutamate uptake in the human brain

Cited by 44 publications

References 13 publications

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type.

Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport

D-aspartate binding to the glutamate uptake site in human brain tissue ? effects of leucotomy

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