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

Abstract

Seizures 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 Aβ depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aβ-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 (PSEN1 p.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 Aβ. We found that all PSEN1-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 PSEN1A246E cells compared to the WT neurons. Thus, we propose that aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aβ, offering prospects for the development of targeted prevention strategies for at-risk individuals.

Cell growth and mitochondrial anomalies in induced pluripotent stem cells with Presenilin 1 mutation

“…We also found that the FAD iPSCs were hyper-sensitive to GSI, leading to further reduction in ATP levels. This suggests that the A246E and L286V PSEN1 mutations behave like partial loss-of-function alleles in iPSCs, according with recent biochemical studies [70,71] . Partial PSEN1 loss-of-function could promote the accumulation of the C99 fragment, which is known to be toxic "inside cells" [71] , prevents normal cleavage and/or expression of Notch [63,64] , and/or perturbs MAM transport [72] .…”