REGIONALLY SELECTIVE ALTERATIONS IN G-PROTEIN SUBUNIT LEVELS IN THE ALZHEIMERS-DISEASE BRAIN

In the present study the relative densities of a number of G protein s ubunits were quantified in membranes prepared from the hippocampus, te mporal cortex and angular gyrus of Alzheimer's disease and control pos t-mortem brain by immunoblotting with specific polyclonal antisera aga inst G(s alpha), G(i alpha), G(i alpha-1), G(o alpha) and G(beta) prot ein subunits. In addition, basal, G(s)-stimulated and G(i)-inhibited a denylyl cyclase activities were measured in the same hippocampal membr ane samples. Densitometric analysis of the immunoblot data revealed a 58% reduction in the levels of G(i alpha), and a 75% reduction in the levels of G(i alpha-1), in the Alzheimer's disease temporal cortex. G( i alpha) levels were reduced, by 37% in the angular gyrus of the Alzhe imer's disease cases. The ratio of large to small molecular weight iso forms of the G(s alpha) subunit was significantly increased in both th e hippocampus and the angular gyrus of the Alzheimer's disease samples when compared to control values, although the difference in individua l G(s alpha) isoform levels did not attain statistical significance wh en comparing groups. No statistically significant differences were obs erved in G(o alpha) or G(beta) levels when comparing control and Alzhe imer's disease cases. G(s)-stimulated adenylyl cyclase activity was si gnificantly reduced in the Alzheimer's disease samples compared to con trols, whereas G(i)-inhibited adenylyl cyclase activity was unchanged. No significant differences were observed between the control and Alzh eimer's disease samples for either basal or forskolin stimulated adeny lyl cyclase activity. The ratio of hippocampal G(s)-stimulated to basa l adenylyl cyclase activity correlated significantly with the large to small G(s alpha) subunit ratio. We conclude that G protein subunit le vels are selectively altered in different regions of the Alzheimer's d isease brain. These alterations may contribute to the functional chang es observed in the CNS in Alzheimer's disease by modifying a number of signal transduction pathways.