Beta-amyloid and the cerebral plaques that it forms are likely either the direct or indirect cause of Alzheimer's disease. This small, 43 amino acid residue peptide is produced in both the central nervous system and peripheral tissues by cleavage from a cell-surface precursor protein. Thus, soluble beta-amyloid exists free in the blood and cerebrospinal fluid and it eventually deposits as ~insoluble"""""""" aggregates to form amyloid plaques in the brain. The hypothesis to be tested suggests that specific antibodies directed against this beta-amyloid peptide can be used either systemically or intracerebrally to disrupt plaque formation and possibly dissolve existing plaques. Soluble and insoluble forms of beta-amyloid within the brain of Alzheimer's patients appear to be in dynamic equilibrium and these may also exchange with beta-amyloid in the blood stream. Accordingly, plaque growth will be curtailed and plaques should gradually dissolve when that equilibrium is displaced by reducing soluble beta-amyloid levels. Depletion will be accomplished by using highly specific anti-beta-amyloid antibodies to tie up or permanently modify beta-amyloid in either the brain or peripheral circulation. Antibodies may function systemically but also can be infused intracerebrally or targeted into the brain using a vectorized bispecific antibody delivery system. Appropriate peptide and transition state peptide analog antigens have been designed to generate either conventional or catalytic anti-beta-amyloid antibodies. Monoclonal antibodies have been produced and chacterized by ELISA and proteolytic assays to select those showing high-affinity binding to beta-amyloid, or catalytic activity, or an ability to dissolve beta-amyloid aggregates. Vectorized bispecific antibodies were formed by coupling the anti-beta-amyloid antibodies to an anti-transferrin receptor antibody which can cross the blood-brain barrier by transcytosis. Systemic and intracerebral anti-beta-amyloid antibodies will be tested using an established colony of transgenic mice that express the human amyloid precursor protein and produce beta-amyloid peptide deposits in the brain at -11 months of age. Beta-amyloid antigens or antibodies will be administered to young and old transgenic mice by periodic i.p. injection either before or after the onset of plaque development. Intracerebral treatment will be by direct infusion into cannulated mice or by using the vectorized reagents. Treated mice will be compared to control transgenic mice in terms of the number and size of plaques in brain sections and the level of B-amyloid peptides in brain extracts. These expressly designed antigens, anti-beta-amyloid antibodies and vectorized anti-beta-amyloid antibodies provide a novel basis for the immunotherapy of Alzheimer's disease.