Communicated by Richard M. Krause, February 6, 1986 ABSTRACT The relationship of the neurofibrillary tangle, found in Alzheimer disease and aged brains, to normal or abnormal cytoskeletal proteins remains elusive. Although immunohistochemical studies have yielded disparate results, most antigenic determinants localized to neurofibrillary tangles are cytoskeletal constituents normally present in neuronal perikarya or dendrites. We report light and electron microscopic immunolabeling of neurofibrillary tangles by a monoclonal antibody to the microtubule-associated protein tau (r). Dephosphorylation of tissue slices not only increased the number of r-positive tangles but also produced marked positive immunoreactivity of neuritic plaques. The localization of ;, an axonal protein, to neurofibrillary tangles in the perikaryon in particular suggests that abnormal synthesis, modification, or aggregation of r may Induce aberrant cytoskeletal-cell organelle interactions, subsequent Interference with axonal flow, and resultant tangle formation.
1 A cloned 5-HT1c receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine Di-selective benzazepines at the 5-HT1c receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1c receptors was measured in the choroid plexus of the pig. 3 The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1c receptor. 4 Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1c receptors in the choroid plexus of the pig (K1 = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (K, = 2.0-2.2 pM). 5 It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.
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