AMPA-selective glutamate receptor subtype immunoreactivity in the hippocampal formation of patients with Alzheimer's disease.
Immunocytochemical techniques were employed in order to examine the distribution and relative intensity of the AMPA receptor subunits GluR1 and GluR2/3 within the hippocampal formation of normal controls and Alzheimer's disease (AD) cases. Throughout our investigation we examined cases exhibiting a wide range of pathologic severity, thus allowing us to correlate our immunohistochemical data with the extent of pathology. Specifically, we investigated the distribution of these receptor subunits in hippocampal sectors that are particularly vulnerable to AD pathology (i.e., CA1 and subiculum) and compared these findings with those obtained following examination of sectors that are generally resistant to pathologic change (i.e., CA2/3, dentate gyrus). Within vulnerable sectors we observed a variable loss of GluR1 and GluR2/3 immunolabeling. The degree to which these proteins were reduced appeared to correlate with the extent of neurofibrillary pathology and cell loss. Despite the loss of labeled cells, the intensity of immunolabeling within the remaining neurons was comparable with, and in many instances even greater than, that observed in control cases. Within resistant sectors, the distribution of immunoreactive elements was comparable in both case groups yet the intensity of immunolabeling was markedly increased in AD cases, particularly in the molecular layer of the dentate gyrus and in the stratum lucidum of CA3 (i.e., the termination zones of perforant pathway and mossy fibers). In addition, within AD cases dramatic increases were observed within the supragranular and polymorphic layer of the dentate gyrus (i.e., the terminal zones of sprouting mossy fiber collaterals). The increase in GluR1 and GluR2/3 immunolabeling is hypothesized to occur in response to the deafferentation of selected glutamatergic pathways. Moreover, our data support that hippocampal plasticity is preserved, even in severe AD cases, and suggest a critical role for AMPA receptor subunits in this plasticity and in maintaining hippocampal functioning.
Ikonomovic
M D
MD
Neurosciences Research Center, Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania 15212-9986, USA.
Sheffield
R
R
Armstrong
D M
DM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000918:Antibody Specificity; D001345:Autoradiography; D018891:Dentate Gyrus / Q000737:chemistry / Q000648:ultrastructure; D005260:Female; D006624:Hippocampus / Q000737:chemistry*; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009473:Neuronal Plasticity / Q000502:physiology; D009929:Organ Size; D018091:Receptors, AMPA / Q000032:analysis / Q000276:immunology*
D018091:Receptors, AMPA