期刊
CELL REPORTS
卷 32, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108169
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资金
- Canadian Institutes of Health Research [PJT-169174, PJT-168968, PJT-156153, FDN-148471, PJT-152914]
- National Institutes of Health [R01 HL057832, R01 GM111397]
- Heart and Stroke Foundation Chair in Cardiovascular Research
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 beta-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-beta-amyloid-targeted anti-AD strategy.
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