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

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

Cell reports (2020-09-24)
Jinjing Yao, Bo Sun, Adam Institoris, Xiaoqin Zhan, Wenting Guo, Zhenpeng Song, Yajing Liu, Florian Hiess, Andrew K J Boyce, Mingke Ni, Ruiwu Wang, Henk Ter Keurs, Thomas G Back, Michael Fill, Roger J Thompson, Ray W Turner, Grant R Gordon, S R Wayne Chen
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
NS5806, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
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1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose, purum, ≥98.0% (TLC)
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Tetraethylammonium chloride, ≥98% (titration)
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D(−)-2-Amino-5-phosphonopentanoic acid, NMDA receptor antagonist