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

ABSTRACT: 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-? (A?) peptide, the primary component of senile plaques associated with AD. Reducing A? 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? peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of A?. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of A?. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce A? peptide and that promoting the production of this isoform with an SSO can reduce A? in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce A? as a potential approach for treating AD.

SUBMITTER: Chang JL 

PROVIDER: S-EPMC5986716 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature