Dataset Information

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

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Publications

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

Chang Jennifer L JL Hinrich Anthony J AJ Roman Brandon B Norrbom Michaela M Rigo Frank F Marr Robert A RA Norstrom Eric M EM Hastings Michelle L ML

Molecular therapy : the journal of the American Society of Gene Therapy 20180306 6

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-β (Aβ) peptide, the primary component of senile plaques associated with AD. Reducing Aβ production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching a ...[more]

PMID: 29628304

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Project description:The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer's disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the 'amyloidogenic' proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the 'non-amyloidogenic' pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.

Dataset Information

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

Publications

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

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