Background-Arrhythmias associated with QT prolongation on the ECG often lead to sudden unexpected death in epilepsy.The mechanism causing a prolongation of the QT interval during epilepsy remains unknown. Based on observations showing an upregulation of neuronal sodium channels in the brain during epilepsy, we tested the hypothesis that a similar phenomenon occurs in the heart and contributes to QT prolongation by altering cardiac sodium current properties (I Na ). Methods and Results-We used the patch clamp technique to assess the effects of epilepsy on the cardiac action potential and I Na in rat ventricular myocytes. Consistent with QT prolongation, epileptic rats had longer ventricular action potential durations attributable to a sustained component of I Na (I NaL ). The increase in I NaL was because of a larger contribution of neuronal Na channels characterized by their high sensitivity to tetrodotoxin. As in the brain, epilepsy was associated with an enhanced expression of the neuronal isoform Na V 1.1 in cardiomyocyte. Epilepsy was also associated with a lower I Na activation threshold resulting in increased cell excitability. Conclusions-This is the first study correlating increased expression of neuronal sodium channels within the heart to epilepsy-related cardiac arrhythmias. This represents a new paradigm in our understanding of cardiac complications related to epilepsy. (Circ Arrhythm Electrophysiol. 2015;8:912-920.

BackgroundThe Aβ peptide that accumulates in Alzheimer’s disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by β- and γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Aβ production.ResultsIn this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Aβ, while knockdown of LRP10 expression increases Aβ production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP β-cleavage into Aβ. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD.ConclusionsThe present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer’s disease.

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