Distribution of glutamate receptor subunit NMDAR1 in the hippocampus of normal elderly and patients with Alzheimer's disease

Abstract

Immunocytochemical techniques were employed to study the distribution and cytological features of NMDAR1-immunoreactive elements in the human hippocampal formation. Subjects with Alzheimer's disease (AD), presenting with a wide range of neuropathology and classified into six Braak stage (I-VI), and nondemented age-matched controls were examined. In control cases, the most intense NMDAR1 immunoreactivity was observed within the soma and dendrites of granule cells in the dentate gyrus and pyramidal neurons in Ammon's horn. Whereas small variations in the pattern of immunoreactivity were noted in control cases, AD subjects were characterized with intersubject variability which in most instances correlated with neuropathologic severity. For example, AD cases, particularly those with mild/modest pathology (Braak I-III), were indistinguishable from controls in the overall pattern of immunolabeling. In contrast, in those more severe AD cases (Braak IV-VI) the intensity of immunolabeling within the CA fields was greater than observed in controls and those with mild AD pathology. In addition, in pathologically severe cases numerous NMDAR1-positive pyramidal neurons were characterized by unique morphologic features including long and often tortuous apical dendrites. These latter findings were most prevalent in the CA1 region and subiculum. In contrast to the marked increase in immunolabeling in the CA fields, in the dentate gyrus we observed a reduction in NMDAR1 labeling particularly within the outer molecular layer (i.e., termination zone of the perforant pathway). This latter region was also the site of a number of NMDAR1-labeled plaques. Notably, the overall pattern of NMDAR1 immunoreactivity is distinct from that observed with antibodies against AMPA receptor subunits and suggests a differential role of various inotropic glutamate receptors in hippocampal plasticity in AD.