Carvedilol suppresses ryanodine receptor-dependent Ca2+ bursts in human neurons bearing PSEN1 variants found in early onset Alzheimer’s disease

• Published in: PloS one Vol. 19; no. 8; p. e0291887
• Main Authors: Hori, Atsushi, Inaba, Haruka, Hato, Takashi, Tanaka, Kimie, Sato, Shoichi, Okamoto, Mizuho, Horiuchi, Yuna, Paran, Faith Jessica, Tabe, Yoko, Mori, Shusuke, Rosales, Corina, Akamatsu, Wado, Murayama, Takashi, Kurebayashi, Nagomi, Sakurai, Takashi, Ai, Tomohiko, Miida, Takashi
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 22.08.2024; Public Library of Science (PLoS)
• Subjects: Acids; Age; Alzheimer's disease; Animal models; Antibodies; Antigens; Aqueous solutions; Biology and Life Sciences; Blocking effects; Brain; Brain-derived neurotrophic factor; Bursts; Calcium (mitochondrial); Calcium (reticular); Calcium channels; Calcium ions; Calcium signalling; Cell culture; Cognition & reasoning; Convulsions & seizures; Endoplasmic reticulum; Epilepsy; Gene expression; Genes; Homeostasis; Inhibitors; Inositol trisphosphate; Inositols; Medicine and Health Sciences; Neurodegenerative diseases; Neurons; Patients; Penicillin; Phenols; Polymers; Presenilin 1; Proteins; Reagents; Receptors; Ryanodine receptors; Seizures; Stem cells; Western blotting; Xestospongin C; United Kingdom > UK; United States > US; Japan; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0291887

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 β (Aß) depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aß-independent mechanisms. Various studies using animal models have shown that Ca2+ is released 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 Presenilin-1 variants (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 Aß. We found 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, an RyR2 inhibitor, and VK-II-86, an analog of carvedilol without the β-blocking effects, sufficiently eliminated the abnormal Ca2+ bursts. In contrast, Dantrolene, an inhibitor of RyR1 and RyR3, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The Western blotting showed that RyR2 expression was not affected by PSEN1 p.A246E, suggesting that the variant may activate the RyR2. 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 Aß, offering prospects for the development of targeted prevention strategies for at-risk individuals.