RODENT MODELS OF ALZHEIMERS-DISEASE - RAT A-BETA INFUSION APPROACHES TO AMYLOID DEPOSITS

The development of rodent models for Alzheimer's disease is a critical step for both understanding the disease and developing therapeutic dr ugs. Transgenic and knockout mouse models will elucidate some importan t aspects of the etiology of the disease and the development of pharma ceutical treatments. Here, we will focus on the advantages of nontrans genic models. In nontransgenic rat models, intraventricular infusion o f A beta 1-40 (alone) generally results in diffuse deposition of A bet a with very few focal plaque-like amyloid deposits after a 30-day intr aventricular infusion. However, we have recently found that large numb ers of scattered A beta immunoreactive plaque-like deposits can be pro duced in retired female Sprague-Dawley rat breeders using intraventric ular infusion of A beta combined with neuropil injection of transformi ng growth factor beta 1(TGF beta). A beta that was not associated with the large deposits was often immunolocalized with neurons and cell pr ocesses. Immunogold electron microscopy demonstrated the presence of A beta in endosome/lysosomes of neuronal processes and glia and basal l amina. In some cases this labeling was clearly in lysosomes of degener ating neurites. This model allows one to introduce A beta and other pl aque-associated factors without overexpression of potentially confound ing APP domains. We conclude that A beta infusion models will be a use ful complement to transgenic approaches to Alzheimer's pathology.