Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production

Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-beta (A beta) peptide, the primary component of senile plaques associated with AD. Reducing A beta production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for A beta peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of A beta. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of A beta. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce A beta peptide and that promoting the production of this isoform with an SSO can reduce Ab in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Ab as a potential approach for treating AD.