Regionally selective alterations in G protein subunit levels in the Alzheimer's disease brain

Abstract

In the present study the relative densities of a number of G protein subunits were quantified in membranes prepared from the hippocampus, temporal cortex and angular gyrus of Alzheimer's disease and control post-mortem brain by immunoblotting with specific polyclonal antisera against G sα, G iα, G iα-1, G oα and G ß protein subunits. In addition, basal, G s-stimulated and G i-inhibited adenylyl cyclase activities were measured in the same hippocampal membrane samples. Densitometric analysis of the immunoblot data revealed a 58% reduction in the levels of G iα, and a 75% reduction in the levels of G iα-1, in the Alzheimer's disease temporal cortex. G iα levels were reduced, by 37% in the angular gyrus of the Alzheimer's disease cases. The ratio of large to small molecular weight isoforms of the G sα subunit was significantly increased in both the hippocampus and the angular gyrus of the Alzheimer's disease samples when compared to control values, although the difference in individual G sα isoform levels did not attain statistical significance when comparing groups. No statistically significant differences were observed in G oα or G ß levels when comparing control and Alzheimer's disease cases. G s-stimulated adenylyl cyclase activity was significantly reduced in the Alzheimer's disease samples compared to controls, whereas G i-inhibited adenylyl cyclase activity was unchanged. No significant differences were observed between the control and Alzheimer's disease samples for either basal or forskolin stimulated adenylyl cyclase activity. The ratio of hippocampal G s-stimulated to basal adenylyl cyclase activity correlated significantly with the large to small G sα subunit ratio. We conclude that G protein subunit levels are selectively altered in different regions of the Alzheimer's disease brain. These alterations may contribute to the functional changes observed in the CNS in Alzheimer's disease by modifying a number of signal transduction pathways.