DOI 10.1007/s00702-004-0243-7 J Neural Transm (2005) 112: 1049–1056 Relationship between Alzheimer’s disease clinical stage and Gq/11 in subcellular fractions of frontal cortex J. F. Kelly, K. Storie, C. Skamra, J. Bienias, T. Beck, and D. A. Bennett Rush Alzheimer’s Disease Center, Rush University Medical Center, Armour Academic Building, Chicago, IL, USA Received April 20, 2004; accepted October 10, 2004 Published online December 7, 2004; # Springer-Verlag 2004 Summary. Alzheimer’s disease (AD) is associated with impaired coupling of cell surface muscarinic cholinergic receptors to G proteins of the Gq=11 class in brain. This alteration may contribute to progression of cognitive impairment during the course of the disease. We hypothesized that increasing severity of cognitive impairment would be related to decreased levels of Gq=11 detected in key subcellular fractions made from postmortem brain tissue. In this study, we used Western blotting to determine the quantity of Gq=11a in P2, synaptic plasma membrane, cytoplasm, microsomal membrane, and lipid raft fractions prepared from superior frontal cortex gray matter of 25 patients with clinical AD confirmed by post-mortem examination. Multiple linear regression analysis that adjusted for age, sex, and education showed a linear relationship between frontal cortex synaptic plasma membrane Gq=11a levels and severity of cog- nitive impairment determined by Mini Mental State score measured proximate to death. Keywords: G proteins, cognition, lipid rafts. Introduction A number of studies have shown that Alzheimer’s disease (AD) is associated with reduced coupling of muscarinic cholinergic receptors to G proteins in postmortem brain tissue (Flynn et al., 1991; Wang and Friedman, 1994; Cutler et al., 1994; Ladner et al., 1995; Ferrari-DeLeo et al., 1995; Jope et al., 1997). However, the mechanisms contributing to this change remain unclear. Muscarinic cholinergic receptors activate heterotrimeric G proteins of the Gi=o and Gq=11 subtypes that modulate the activity of second mes- sengers and ion channels involved in learning and memory processes. Avail- able data suggest that m2 muscarinic receptor coupling via Gi=o is preserved in Alzheimer’s disease (Cowburn et al., 1992), but m1 muscarinic receptor