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

Abstract

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...

Differential Regulation of Glutamate Receptors in Alzheimer’s Disease

“…Kainate binding is significantly reduced in the parahippocampal gyrus, while in a number of other hippocampal areas (e.g., dentate gyrus, CA3), the binding of ligand is minimally altered in AD [80]. In contrast to hippocampal regions, kainate receptor binding is significantly increased by approximately 70% in deep layers of the AD frontal cortex compared with controls and there is a positive correlation between kainate binding and the senile plaque number in deep cortical layers [82]. However, in caudate nucleus, kainate binding is unaltered [94].…”

“…In addition, the same group reported that there is also decreased ligand binding in the cerebellum in AD [81]. However, other studies have demonstrated that the binding of ligand is unaltered in frontal cortex [82] and increased in the infragranular layer [83].…”

Possible roles ofl-phosphoserine in the pathogenesis of Alzheimer’s disease

“…Consistent with this is the finding that presynaptic Glu-containing terminals, as measured by the marker o- [ 3H]aspartate, appear to be decreased in AD (Proctor et al, 1988b;Simpson et al, 1988;Chalmers et al, 1990). Despite this decrement in presynaptic glutamatergic markers, postsynaptic elements remain largely intact (Mouradian et a!., 1988;Simpson et al, 1988;Cotman et al, 1989;Cowburn et al, 1989;Chalmers et al, 1990), although evidence to suggest that the glycine regulatory site of the N-methyl-D-aspartate (NMDA) receptor complex is abnormal has been found by some (Procter et al, 1989a, b;Steele et al, 1989), but not all investigators (Ninomiya et a!., .1990). These findings have led to the suspicion that some other endogenous metabolite may be playing a pathogenetic role in AD via action at Glu receptors.…”

Neuropathobiology of Senile Dementia and Mechanism of Action of Nootropic Drugs

“…Various alterations were described concerning the density and binding capacity of EAA receptors in Alzheimer's disease brains (Chalmers et al 1990;Geddes et al 1992;Greenamyre et al 1987;Jansen et al 1990). In spite of some contradictory results in these studies, it seems reasonable to hypothesise that the excitotoxicity, mediated by EAA, may playa role in the neuropathobiology of Alzheimer's disease (Deutsch & Morihisa 1988;Greenamyre & Young 1989).…”