title: Disturbances in signal transduction mechanisms in Alzheimer's disease.
abstract: Many of the treatments directed towards alleviation of symptoms in Alzheimer's disease assume that target receptor systems are functionally intact. However, there is now considerable evidence that this is not the case. In human post-mortem brain tissue samples, the function of the GTP-binding protein Gs in regulating adenylyl cyclase is severely disabled, whereas that of Gi is intact. This difference in the function of the two G-protein types is also found in G-protein regulation of high- and low-affinity receptor recognition site populations. Measurement of G-protein densities using selective antibodies has indicated that the dysfunction in Gs-stimulation of cAMP production correlates with the ratio of the large to small molecular weight isoforms of the Gs alpha subunit. With respect to intracellular second messenger effects, there is a dramatic decrease in the density of brain receptor recognition sites for Ins(1,4,5)P3 that is not accompanied by a corresponding change in the Ins(1,3,4,5)P4 recognition site density. Protein 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 also seen in cultured fibroblasts from Alzheimer's disease patients, indicating that they are neither restricted to areas of histopathological change, nor non-specific changes found late in the course of the disease. Cellular models to investigate the relation between amyloid production and deficits in signal transduction are also discussed.
authors.affiliation: Alzheimer's Disease Research Centre, Department of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Sweden.
authors.forename: C J
authors.initials: CJ
authors.lastname: Fowler
authors.forename: R F
authors.initials: RF
authors.lastname: Cowburn
authors.forename: A
authors.initials: A
authors.lastname: Garlind
authors.forename: B
authors.initials: B
authors.lastname: Winblad
authors.forename: C
authors.initials: C
authors.lastname: O'Neill
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D000682:Amyloid / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010716:Phosphatidylinositols / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D015290:Second Messenger Systems; D011984:Sensory Receptor Cells / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D000682:Amyloid; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010716:Phosphatidylinositols; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D011493:Protein Kinase C; D019204:GTP-Binding Proteins