Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice
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Abstract
beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor
protein (APP). Abeta 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 Abeta region of the APP gene given with or without
antibody directed at Abeta could reverse the elevated protein levels of APP and the
behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses
APP. We found that intracerebroventricular (ICV) administration of antibody with either
of two AOs directed at the midregion of Abeta 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 Abeta region of APP can
reduce APP levels in the brain and reverse deficits in learning and memory.