Effects of postmortem interval, age, and Alzheimer's disease on G-proteins in human brain

Heterotrimeric G-proteins are critical components in many receptor-coupled signal transduction systems, and altered levels and functions of G-proteins have been implicated in several neurological disorders, including Alzheimer's disease. Investigations in postmortem human brain provide a direct approach to study G-protein involvement in neurological disorders. Therefore, the effects of postmortem interval, aging, and Alzheimer's disease on G-protein levels were determined in postmortem human brain and an assay to measure activation of G-proteins was developed. Within the postmortem interval range of 5 to 21 h, the levels of G alpha i1, G alpha i2, G alpha s, and G beta were stable, whereas G alpha q and G alpha o decreased slightly, in human prefrontal cortex. In subjects aged 19 to 100 y, decreased levels of G alpha q and G alpha o were significantly correlated with increased age, but levels of the other G-protein subunits did not vary. In Alzheimer's disease prefrontal cortex, superior temporal gyrus, and occipital cortex, all G-protein subunit levels were equivalent to those in matched controls except for a slight deficit in G alpha i1. An ELISA assay using selective antibodies was used to measure [35S]GTP gamma S binding to G alpha o and G alpha i1. Binding was proportional to the concentration of GTP-gamma S and was concentration-dependently stimulated by mastoparan equivalently in control and Alzheimer's disease prefrontal cortical membranes.