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

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.

Graphical Abstract

In Brief

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.

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 26 September 2020

Publication date (Print): 22 September 2020

Publication date PMC-release: 03 October 2020

Volume: 32

Issue: 12

Page: 108169

Affiliations

[1 ]Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada

[2 ]Medical School, Kunming University of Science and Technology, Kunming 650504, China

[3 ]Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada

[4 ]Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada

[5 ]Department of Chemistry, University of Calgary, Calgary, AB T2N 1N4, Canada

[6 ]Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL 60612, USA

[7 ]These authors contributed equally

[8 ]Lead Contact

Author notes

AUTHOR CONTRIBUTIONS

J.Y., B.S., A.I., X.Z., H.t.K., T.G.B., M.F., R.J.T., R.W.T., G.R.G., and S.R.W.C. designed the research. J.Y., B.S., A.I., X.Z., W.G., Z.S., Y.L., F.H., A.K.J.B., M.K., and R.W. performed the research. J.Y., B.S., X.Z., W.G., Z.S., M.N., R.W., and S.R.W.C. analyzed the data, J.Y., B.S., H.t.K., T.G.B., M.F., R.J.T., R.W.T., G.R.G., and S.R.W.C. wrote the paper.

[* ]Correspondence: swchen@ 123456ucalgary.ca

Article

Manuscript ID: NIHMS1631917

DOI: 10.1016/j.celrep.2020.108169

PMC ID: 7532726

PubMed ID: 32966798

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Categories

Subject: Article