Density and distribution of NMDA receptors in the human hippocampus in Alzheimer's disease

Geddes, James W.; Chang-Chui, Helena; Cooper, Suzanne M.; Lott, Ira T.; Cotman, Carl W.

doi:10.1016/0006-8993(86)90611-6

Cited by 204 publications

(58 citation statements)

References 22 publications

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“…It therefore seems important to consider the findings of the present study in the context of the in situ anatomy and physiology of the hippocampus. Within the hippocampus glutamatergic afferents to pyramida1 neurons are believed to be localized to distal regions of the dendrites (Isaacson and Pribram, 1975;Monaghan and Cotman, 1982;Collinridge et al, 1983a, b;Harris and Cotman, 1983;Sawada et al, 1983;Foster and Fagg, 1984;Greenamyre et al, 1984;Geddes et al, 1986). The observation in the present study of a pronounced sensitivity of dendritic versus axonal outgrowth to glutamate is consistent with a localization of functional glutamate receptors on dendrites but not the axon.…”

Section: Discussionsupporting

confidence: 84%

“…Glutamate action on pyramidal neurons may mediate fundamental brain processes such as learning and memory (see Lynch, 1986, for review). Somewhat paradoxically, glutamate may also be involved in the degeneration of pyramidal neurons seen in several diseases including epilepsy (Schwartz et al, 1984) Huntington's disease (Coyle and Schwartz, 1976), Alzheimer's disease (Geddes et al, 1986;Maragos et al, 1987) and stroke (Rothman, 1984;Simon et al, 1984b). It is clear that high levels of glutamate and related excitatory amino acids (EAAs) including kainic acid (KA), quisqualic acid (QA), and N-methyl-D-aspartic acid (NMDA) can cause a striking neurodegeneration of specific neurons, including hippocampal pyramidal neurons (Olney, 1978(Olney, , 1983Coyle et al, 1981;Choi et al, 1987).…”

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confidence: 99%

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Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons

1988

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The present study examined the effects of glutamate on the outgrowth of dendrites and axons in isolated hippocampal pyramidal-like neurons in cell culture. During the first day of culture the survival and outgrowth of these neurons was unaffected by high concentrations (up to 1 nM) of glutamate, quisqualic acid (QA), kainic acid (KA), and N- methyl-D-aspartic acid. Beginning on day 2 of culture high levels of glutamate, KA and QA were toxic to the majority of pyramidal neurons, while subtoxic levels of these agents caused a well-defined, dose- dependent, sequence of effects on dendritic outgrowth. At increasing concentrations of glutamate, QA, and KA, the following events were observed: (1) dendritic outgrowth rates were reduced, while axonal elongation rates were unaffected; (2) dendritic length was reduced, while axons continued to grow; (3) dendrites regressed dramatically, and axonal outgrowth rate was reduced. These dendrite-specific effects of glutamate were apparently mediated at the growth cones since focal application of glutamate to individual dendritic growth cones resulted in suppression of growth cone activity and a regression of the dendrite; axons were unaffected by focal glutamate application. Pharmacological tests using glutamate receptor agonists and antagonists demonstrated that receptors of the KA/QA type mediated the glutamate effects on outgrowth and survival. The calcium channel blocker Co2+ prevented both glutamate neurotoxicity and glutamate-induced dendritic regression. Ionophore A23187 and elevations in extracellular K+ levels each caused a dose-dependent series of outgrowth and survival responses similar to those caused by glutamate. Taken together, these results indicate that activation of glutamate receptors leads to the opening of voltage-dependent calcium channels; the resulting increases in calcium influx lead to the observed alterations in dendritic outgrowth and neuronal survival.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons

1988

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“…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.…”

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confidence: 74%

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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“…This delayed the postmortem cooling of the mouse brain in order to more closely approximate the human brain cooling curve (Geddes et al, 1986;Schwab et al, 1994). Postmortem intervals (PMIs) used were chosen based on the minimum and maximum human PMIs obtained from the UK ADC found in Table I and Table II.…”

Section: Mouse Brain Tissuementioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Density and distribution of NMDA receptors in the human hippocampus in Alzheimer's disease

Cited by 204 publications

References 22 publications

Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons

Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons

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

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

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