Phenotypic down-regulation of glutamate receptor subunit GluR1 in Alzheimer's disease.

Glutamate receptors play crucial roles in cognition and memory. We have quantitated the protein levels of alpha-amino-isoxazolepropionic acid (AMPA)-type (GluR1) and N-methyl-D-aspartate-type (NMDAR1) glutamate receptors in postmortem brain tissues of patients with Alzheimer's disease and age-matched controls using western blotting. The bolts carrying fully denatured proteins were probed with antibodies specific to their carboxyl terminus of these receptors. In Alzheimer's disease, GluR1 levels were significantly decreased in the entorhinal cortex and dentate gyrus, but not in the motor cortex. In contrast, levels of NMDAR1 were not altered in the dentate gyrus, suggesting that GluR1 expression was specifically diminished in this structure that is known to be preserved histologically in patients. However, the results of immunocytochemical examination confirmed a previous controversial report: GluR1-immunoreactive structures were labeled rather intensely in the molecular layer of the dentate gyrus of Alzheimer's patients. Interestingly, levels of a postsynaptic density protein named SAP97, which recognizes and potentially masks the epitope region of GluR1, was positively correlated with those of GluR1 protein in the control group, but not in the patient group. Thus, the enhanced GluR1-like staining in Alzheimer's disease might be ascribed to the hampered interaction between SAP97 and GluR1 leading to epitope unmasking of GluR1 on tissue sections. These findings indicate that abnormal expressions of the AMPA receptor and its interacting PSD molecule are associated with Alzheimer's disease and implicated in pathophysiology of this disease.