Several genes located in the obligate region of chromosome 21 for Down syndrome (DS), including the APP gene, have also been implicated in the etiology of Alzheimer's disease (AD). We reported abnormal patterns of adenylyl cyclase (AC) functioning in several brain areas of the DS mouse model Ts65Dn and of two children with DS (Lumbreras et al., SFN 1999), and of phospholipase C (PLC) in Ts65Dn mice (Sallés et al., SFN 1998). We examine AC and PLC activities in cerebral cortex of 4 adults with DS, 4 with AD, and 4 controls (C). AC signaling was assessed by determining cAMP formation in isolated membranes under basal conditions and after stimulation with GTP γS (10 μM), norepinephrine (NE, 100 μM), SKF38393 (10 μM) and forskolin (FK, 100 μM). PLC was assessed by analyzing the breakdown of [3H] PIP2 into [3H]inositol phosphates under basal conditions and after stimulation with GTPγS (3 μM), 5-methyltryptamine (300 μM), carbachol (1 mM) and calcium (10 μM). Basal production of cAMP was significantly red...