| First Author | Yao J | Year | 2020 |
| Journal | Cell Rep | Volume | 32 |
| Issue | 12 | Pages | 108169 |
| PubMed ID | 32966798 | Mgi Jnum | J:311228 |
| Mgi Id | MGI:6714752 | Doi | 10.1016/j.celrep.2020.108169 |
| Citation | Yao J, et al. (2020) Limiting RyR2 Open Time Prevents Alzheimer's Disease-Related Neuronal Hyperactivity and Memory Loss but Not beta-Amyloid Accumulation. Cell Rep 32(12):108169 |
| abstractText | 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. |
