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 antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Aβ peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of Aβ. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of Aβ. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce Aβ peptide and that promoting the production of this isoform with an SSO can reduce Aβ in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Aβ as a potential approach for treating AD.
This paper presents data related to the article “A method for easily customizable gradient gel electrophoresis” (A.J. Miller, B. Roman, E.M. Norstrom, 2016) [1]. Data is presented on the rate of electrophoretic migration of proteins in both hand-poured and commercially acquired acrylamide gradient gels. For each gel, migration of 9 polypeptides of various masses was measured upon completion of gel electrophoresis. Data are presented on the migration of proteins within separate lanes of the same gel as well as migration rates from multiple gels.
To date, few patients with anti-SAE1 dermatomyositis (DM) have been described, and usually in large descriptive cohort studies including all DM subtypes. Thus, it is increasingly important to further describe this rare subtype to solidify cutaneous findings, associated symptoms, and potential therapeutic options. Herein, this case series describes three patients with anti-SAE1 DM with respect to their clinical and laboratory findings, and also their response to treatment. All three patients eventually presented with classic cutaneous manifestations of dermatomyositis, however, Case 2 presented initially with cutaneous manifestations not described in the literature. Furthermore, two patients presented with dysphagia, with Case 2 experiencing a life-threatening dysphagia not typically described in the literature. Two of three patients also presented with early signs of interstitial lung disease. Lastly, cutaneous disease was only responsive to immunosuppressants in one patient. Unfortunately, this observational case-series consisted of only three patients, limiting the generalizability of our results. However, this study provides further support of the recalcitrant nature of this DM subtype, and commonly affected extracutaneous systems including the gastrointestinal and pulmonary systems. Larger studies of this patient population are needed to further confirm our associated findings.
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