Cholinergic loss and amyloid formation are important hallmarks of Alzheimer's Disease (AD), however it is not yet known whether cortical cholinergic dysfunction and amyloidogenesis interact to produce cognitive impairments. In the present study, we have investigated this possibility by combining selective immunotoxic lesioning of the basal forebrain cholinergic system with the intracerebral injection of the pre-aggregated beta-amyloid (25–35). Adult rats were injected with sub-symptomatic doses of IgG-192-Saporin and/or amyloid peptide intracerebrally. Control animals received similar injections of vehicle alone. Four weeks later, the animals were tested in the Morris Water Maze task, using protocols specifically designed to detect deficits in reference or working memory abilities. After completion of the testing, the brain tissue underwent histo- and immunochemistry or western blot analyses to verify treatments efficacy and selectivity. Animals treated simultaneously with the immunotoxin and the amyloid peptide were seen significantly impaired in the spatial navigation task. By contrast, animals with single injections of either compound did not differ significantly from normal, although in these groups the cholinergic depletion or the amyloid aggregates were evident, the latter being very similar to those seen in AD tissue specimens. The results suggest that an interaction between cholinergic loss and beta amyloid aggregation may take place that in turn produces cognitive dysfunction. Data will be presented concerning the possible protective action of newly synthesised neuroactive compounds.