The microtubule-associated proteins (MAPs), tau and MAP1B are highly regulated during normal neuronal development. Evidence is accumulating suggesting the re-emergence of fetal characteristics in vulnerable neurons involved in Alzheimer's Disease (AD) pathology. Both fetal and adult forms of tau are known to be integral components of the paired helical filament (PHF) and preliminary evidence indicates that AD-affected neurons express high levels of MAP1B. Therefore, we propose to determine the relative amounts of both of these proteins in brain regions and to determine the fetal/adult tau ratios in AD and control brains. Unlike other studies, we will attempt to control for neuronal death by also measuring the amount of neuronal tubulin using a specific monoclonal antibody and expressing the data as ratios of MAP/neuronal tubulin. In order to determine other proteins that may be associated with tau in the PHF or in other aspects of AD pathology, non-tubulin tau interacting proteins (TIPs) will be identified and quantified in AD and control brain. TIPs of demonstrated importance to ADD will be purified and characterized. Microtubule binding studies will be performed using AD and normal soluble tau as well as A68 to ascertain whether the microtubule binding capabilities of these different preparations are altered in the disease state. In addition, existing and novel monoclonal antibodies will be used to measure the amounts of tau in cerebral spinal fluids (CSFs) obtained from AD and control patients to ascertain whether tau can serve as a diagnostic marker for AD. Successful completion of these experiments will aid in establishing the degree to which tau and MAP1B are altered in either their expression, form or interactions in AD pathology.
| Wilson, D M; Binder, L I (1997) Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer's disease. Am J Pathol 150:2181-95 |
| Carmel, G; Mager, E M; Binder, L I et al. (1996) The structural basis of monoclonal antibody Alz50's selectivity for Alzheimer's disease pathology. J Biol Chem 271:32789-95 |
| Wilson, D M; Binder, L I (1995) Polymerization of microtubule-associated protein tau under near-physiological conditions. J Biol Chem 270:24306-14 |
| Brady, R M; Zinkowski, R P; Binder, L I (1995) Presence of tau in isolated nuclei from human brain. Neurobiol Aging 16:479-86 |
| Wang, Y; Loomis, P A; Zinkowski, R P et al. (1993) A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau. J Cell Biol 121:257-67 |
| Greenberg, S G; Davies, P; Schein, J D et al. (1992) Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. J Biol Chem 267:564-9 |
