Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice

beta amyloid protein (A beta) is a 40-43 amino acid peptide derived from am yloid precursor protein (APP). A beta has been implicated as a cause of Alz heimer's disease (AD). Mice with spontaneous or transgenic overexpression o f APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the A beta region of the APP gene given with or without a ntibody directed at A beta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontane ously over-expresses APP. We found that intracerebroventricular (ICV) admin istration of antibody with either of two AOs directed at the midregion of A beta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehi cle were without effect. Three injections of the more potent AO given witho ut antibody reduced APP protein levels by 43-68% in the amygdala, septum, a nd hippocampus. These results show that AO directed at the A beta region of APP can reduce APP levels in the brain and reverse deficits in learning an d memory. (C) 2000 Published by Elsevier Science Inc.