Jinjing Yao 1 , 7 , Bo Sun 1 , 2 , 7 , Adam Institoris 3 , Xiaoqin Zhan 4 , Wenting Guo 1 , Zhenpeng Song 1 , Yajing Liu 1 , Florian Hiess 1 , Andrew K.J. Boyce 4 , Mingke Ni 1 , Ruiwu Wang 1 , Henk ter Keurs 1 , Thomas G. Back 5 , Michael Fill 6 , Roger J. Thompson 4 , Ray W. Turner 4 , Grant R. Gordon 3 , S.R. Wayne Chen 1 , 6 , 8 , *
03 October 2020
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.
Yao et al. show that genetically or pharmacologically limiting the open duration of ryanodine receptor 2 upregulates the A-type potassium current and prevents neuronal hyperexcitability and hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset Alzheimer’s disease mouse model, even with continued accumulation of β-amyloid.