Certain neuropathological lesions characterize the brains of normal aged humans and monkeys, and particularly Alzheimer's disease patients, where the lesions occur much earlier and in far greater numbers. The substantial minority (between 15 and 50%) of Alzheimer cases which appear to be the result of the inheritance of an autosomal dominant mutation indicate that a single genetic defect can cause the neuropathology. Using an immunochemical/ molecular genetic approach, the gene coding for one component of the extracellular protein deposits (termed """"""""amyloid"""""""") of normal aged and Alzheimer's disease brain was cloned, and found to code for a protease inhibitor, alpha 1-antichymotrypsin. Further experiments confirmed the intimate association of this protease inhibitor with the proteinaceous amyloid filaments of normal aged and Alzheimer's disease brain. Most of the next five years will be devoted to determining how alpha 1-antichymotrypsin contributes to amyloid deposition, either directly as a structural amyloid component, or indirectly as a protease inhibitor. For example, the fact that alpha 1- antichymotrypsin is overexpressed in Alzheimer brain suggests that it may prevent the normal clearing of amyloid deposits. Studies will determine the protease targets of alpha 1-antichymotrypsin inhibition in the brain, the cells expressing alpha 1- antichymotrypsin, and any alterations which may arise in the alpha 1-antichymotrypsin gene, its expression, or its encoded protein, during normal aging or Alzheimer's disease. Transgenic mice will be made in which alpha 1-antichymotrypsin will be overexpressed in a regulated manner to determine whether such over-expression leads to neuropathology, and to provide an animal model for testing potential therapeutic approaches to Alzheimer's disease and 'normal' senile neuropathy.
