Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting neurons in macaque and patas monkeys.

A distinct subpopulation of neurons forming long corticocortical projections in the association neocortex is highly vulnerable to the degenerative process in Alzheimer's disease. However, the degree to which age-related molecular and morphologic alterations of identifiable neuronal populations reflects early cellular degeneration leading to functional deficits has not yet been fully investigated in the aging brain. We performed an immunohistochemical analysis of neurons forming short and long corticocortical projections in young and old monkeys using antibodies to the GluR2 and NMDAR1 glutamate receptor subunit proteins. Projection neurons differed in their expression of these receptor subunits, as GluR2 was less prevalent than NMDAR1 among retrogradely labeled neurons. Long and short corticocortical pathways in old animals demonstrated a considerable decrease in the proportions of projection neurons containing GluR2 and NMDAR1, an observation that was particularly consistent in the case of GluR2. No age-related differences were observed in distribution of neurofilament protein in either type of projection neurons. These data suggest that cortical neurons furnishing long and short corticocortical projections display consistent neurochemical changes during aging and that a differential decrease in cellular expression of glutamate receptor subunit proteins occurs. The fact that in aging these neurons have lower levels of GluR2 than in young individuals, but comparatively higher levels of NMDAR1 than GluR2, may render them prone to calcium-mediated excitotoxicity, which in humans may be related to the selective vulnerability of such neurons during the course of Alzheimer's disease. Also, it is apparent that age-related neuronal changes are quite subtle and involve subcellular components of the cortical circuits rather than major morphologic alterations.