DISTURBANCES IN SIGNAL-TRANSDUCTION MECHANISMS IN ALZHEIMERS-DISEASE

Many of the treatments directed towards alleviation of symptoms in Alz heimer's disease assume that target receptor systems are functionally intact. However, there is now considerable evidence that this is not t he case. In human post-mortem brain tissue samples, the function of th e GTP-binding protein G(s) in regulating adenylyl cyclase is severely disabled, whereas that of G(i) is intact. This difference in the funct ion of the two G-protein types is also found in G-protein regulation o f high- and low-affinity receptor recognition site populations. Measur ement of G-protein densities using selective antibodies has indicated that the dysfunction in G(s)-stimulation of cAMP production correlates with the ratio of the large to small molecular weight isoforms of the G(s) alpha subunit. With respect to intracellular second messenger ef fects, there is a dramatic decrease in the density of brain receptor r ecognition sites for Ins(1,4,5)P-3 that is not accompanied by a corres ponding change in the Ins(1,3,4,5)P-4 recognition site density. Protei n kinase C function is also altered in Alzheimer's disease, a finding that may be of importance for the control of beta-amyloid production. These studies indicate that signal transduction processes are severely compromised in Alzheimer's disease. Some of these disturbances are al so seen in cultured fibroblasts from Alzheimer's disease patients, ind icating that they are neither restricted to areas of histopathological change, nor non-specific changes found late in the course of the dise ase. Cellular models to investigate the relation between amyloid produ ction and deficits in signal transduction are also discussed.