Limiting RyR2 Open Time Prevents Alzheimer’s Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation
2020
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
Summary: 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.
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