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 amyloid precursor protein (APP). A beta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of 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 antibody directed at A beta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously over-expresses APP. We found that intracerebroventricular (ICV) administration 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 vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and 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 and memory. (C) 2000 Published by Elsevier Science Inc.