Dataset Information

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

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 ?-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-?-amyloid-targeted anti-AD strategy.

SUBMITTER: Yao J

PROVIDER: S-EPMC7532726 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Yao Jinjing J Sun Bo B Institoris Adam A Zhan Xiaoqin X Guo Wenting W Song Zhenpeng Z Liu Yajing Y Hiess Florian F Boyce Andrew K J AKJ Ni Mingke M Wang Ruiwu R Ter Keurs Henk H Back Thomas G TG Fill Michael M Thompson Roger J RJ Turner Ray W RW Gordon Grant R GR Chen S R Wayne SRW

Cell reports 20200901 12

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 dendriti ...[more]

PMID: 32966798

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Dataset Information

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

Publications

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

Similar Datasets

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