Limiting RyR2 Open Time Prevents Alzheimer's Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation.

Autor:	Yao J; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Sun B; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Medical School, Kunming University of Science and Technology, Kunming 650504, China., Institoris A; Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Zhan X; Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Guo W; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Song Z; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Liu Y; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Hiess F; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Boyce AKJ; Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Ni M; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Wang R; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Ter Keurs H; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Back TG; Department of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada., Fill M; Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL 60612, USA., Thompson RJ; Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Turner RW; Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Gordon GR; Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada., Chen SRW; Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address: swchen@ucalgary.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Sep 22; Vol. 32 (12), pp. 108169.
DOI:	10.1016/j.celrep.2020.108169
Abstrakt:	Neuronal hyperactivity is an early primary dysfunction in Alzheimer's disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ryanodine receptor 2 (RyR2) control of neuronal hyperactivity and AD progression. We show that a single RyR2 point mutation, E4872Q, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset AD mouse model (5xFAD). The RyR2-E4872Q mutation upregulates hippocampal CA1-pyramidal cell A-type K + current, a well-known neuronal excitability control that is downregulated in AD. Pharmacologically limiting RyR2 open time with the R-carvedilol enantiomer (but not racemic carvedilol) prevents and rescues neuronal hyperactivity, memory impairment, and neuron loss even in late stages of AD. These AD-related deficits are prevented even with continued β-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-β-amyloid-targeted anti-AD strategy. Competing Interests: Declaration of Interests We are planning to submit a Provisional Application for Patent, entitled “METHODS OF TREATING ALZHEIMER’S DISEASE OR DELAYING PROGRESSION THEREOF BY LIMITING RYANODINE RECEPTOR OPEN TIME.” (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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