RATIONAL DESIGN OF AN ANIMAL-MODEL FOR ALZHEIMERS-DISEASE - INTRODUCTION OF MULTIPLE HUMAN GENOMIC TRANSGENES TO REPRODUCE AD PATHOLOGY IN A RODENT

A major obstacle to understanding the pathogenesis of Alzheimer's dise ase is the lack of easily studied animal models. Our approach is to ap ply transgenic methods to humanize mice and rats, employing methods th at introduce large genomic transgenes, because this improves the level of transgene protein expression and the tissue specificity of express ion. Our plan is to reproduce AD pathology in rodents by making them t ransgenic for several human proteins involved in AD. This report descr ibes transgenic animal lines that we have produced, and summarizes our current approach and future plans. Two human genes known to be involv ed in AD pathology are the amyloid precursor protein (APP) and the E4 isoform of apolipoprotein E (apoE4). So far, we have produced and anal yzed a transgenic line carrying the entire human APP gene cloned in a yeast artificial chromosome. We have also produced but not yet analyze d a mouse carrying the human apoE4 gene. Work is in progress to produc e a transgenic line carrying a disease-causing mutation in the human A PP gene. As we produce these animals, we are breeding them together, a nd also breeding them with a mouse line that lacks endogenous apoE, to produce an animal model carrying several human proteins whose interac tion is believed to be instrumental in development of AD pathology. Th ese transgenic animals will be useful for dissecting the biochemical a nd physiological steps leading to AD, and for development of therapies for disease intervention.