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

Therapeutic correction of ApoER2 splicing in Alzheimer's disease mice using antisense oligonucleotides.

Apolipoprotein E receptor 2 (ApoER2) is an apolipoprotein E receptor involved in long-term potentiation, learning, and memory. Given its role in cognition and its association with the Alzheimer's disease (AD) risk gene, apoE, ApoER2 has been proposed to be involved in AD, though a role for the receptor in the disease is not clear. ApoER2 signaling requires amino acids encoded by alternatively spliced exon 19. Here, we report that the balance of ApoER2 exon 19 splicing is deregulated in postmortem brain tissue from AD patients and in a transgenic mouse model of AD To test the role of deregulated ApoER2 splicing in AD, we designed an antisense oligonucleotide (ASO) that increases exon 19 splicing. Treatment of AD mice with a single dose of ASO corrected ApoER2 splicing for up to 6 months and improved synaptic function and learning and memory. These results reveal an association between ApoER2 isoform expression and AD, and provide preclinical evidence for the utility of ASOs as a therapeutic approach to mitigate Alzheimer's disease symptoms by improving ApoER2 exon 19 splicing.

Screening for Type 2 Diabetes and Dysglycemia in Saudi Arabia: Development and Validation of Risk Scores.

OBJECTIVE: The prevalence of type 2 diabetes in Saudi Arabia is the highest worldwide after excluding small island nations. We developed and validated a noninvasive screening test based on demographic and clinical data for identifying adults with undiagnosed diabetes and dysglycemia in Saudi Arabia. RESEARCH DESIGN AND METHODS: Data from 1,485 nonpregnant Saudi adults ≥20 years of age without a current diagnosis of diabetes were obtained from urban and rural primary healthcare centers in 2009. Clinical and demographic data were obtained through physician-administered interviews. Oral glucose tolerance test data were used to define diabetes (fasting plasma glucose ≥7.0 mmol/L or 2-h post-load glucose ≥11.1 mmol/L) and dysglycemia (fasting plasma glucose ≥5.6 mmol/L or 2-h post-load glucose ≥7.8 mmol/L). Predictive models were developed using data from 1,435 individuals. Multivariable logistic regression and receiver operating characteristic curves were used to develop and evaluate a separate risk score for both diabetes and dysglycemia. Scores were validated on a hold-out sample of 50 individuals. RESULTS: The risk score for undiagnosed diabetes contained age, history of gestational diabetes, smoking, family history of diabetes, and central obesity with a sensitivity of 76.6% and a specificity of 52.1%. The dysglycemia risk score contained age, gestational diabetes, hypertension, and central obesity with a sensitivity of 71.2% and a specificity of 54.0%. All performed equally well, if not better, in the hold-out sample. CONCLUSIONS: These risk scores can identify Saudi adults with undiagnosed diabetes or dysglycemia and should be validated in prospective studies.