Carvedilol suppresses ryanodine receptor-dependent Ca2+bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Abstract

AbstractSeizures are increasingly being recognized as the hallmark of Alzheimer’s disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid β (Aß) depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aß-independent mechanisms. Indeed, various studies using animal models showed that Ca2+releases from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP3R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca2+signaling in neural cells derived from three early-onset AD patients harboring variants of Presenilin-1 (PSEN1p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal Aß. We found that allPSEN1-mutant neurons, but not wild-type, caused abnormal Ca2+-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, anRyR2 inhibitor, and VK-II-86, an analog of carvedilol without the β-blocking effects, sufficiently eliminated the abnormal Ca2+bursts. In contrast, Dantrolene, a RyR1 inhibitor, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca2+-transporter genes were decreased in PSEN1A246Ecells compared to the WT neurons. Thus, we propose that aberrant Ca2+signaling is a key link between human pathogenicPSEN1variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aß, offering prospects for the development of targeted prevention strategies for at-risk individuals.One Sentence SummaryAberrant Ca2+-signaling causesPSEN1-related early onset Alzheimer’s disease.