Previous studies have shown that disruption of the neuronal cytoskeleton, which normally functions to maintain cytoplasmic compartmentalization, intracellular transport and neuronal morphology, is a key feature of Alzheimer's disease. Paired helical filaments, the primary ultrastructural constituent of neurofibrillary tangles, contain the microtubule associated [protein, tan, as an integral component. Tau and other cytoskeletal proteins are reorganized in Alzheimer's disease, thereby providing potential substrate for widespread degeneration and growth response. Our hypothesis is that degeneration and regeneration are critically dependent on cytoskeletal composition. A major goal of the present study is to establish the precise morphology and distribution of the microtubule-associated proteins MAP2 and tau, and the protein ubiquitin in the medical temporal lobe and their relationship to neurofibrillary tangles, as defined by thioflavine S and Hicks-Gallyas staining, in aged controls and Alzheimer's disease patients. The medical temporal lobe encompasses a range of cortical and subcortical regions fundamental to memory processing which are lesioned in Alzheimer's disease. We will define distribution of tau isoforms because alterations of tau may be important in the formation of paired helical filaments. Differentially affected regions will be examined in patients with Alzheimer's disease of variable severity, duration, and age of onset to determine the chronology of alterations. The distribution of kinases potentially responsible for phosphorylation of tau, such as CaM kinase type II, will be defined. The nature and extent of growth response in Alzheimer's disease will be examined using markers associated with growth cones, including actin, GAP 43, and neural cell adhesion molecule. Specific procedures include immunoperoxidase, immunofluorescence, and immunogold procedures using well characterized antisera. Colocalization studies to determine the interrelationship of cytoskeletal proteins will be performed using double immunofluorescence and immunoperoxidase procedures.
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