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

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          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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          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.

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          Most cited references 104

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          APP processing and synaptic function.

          A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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            Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

            Alzheimer's disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.
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              Relaxation of arterial smooth muscle by calcium sparks.

              Local increases in intracellular calcium ion concentration ([Ca2+]i) resulting from activation of the ryanodine-sensitive calcium-release channel in the sarcoplasmic reticulum (SR) of smooth muscle cause arterial dilation. Ryanodine-sensitive, spontaneous local increases in [Ca2+]i (Ca2+ sparks) from the SR were observed just under the surface membrane of single smooth muscle cells from myogenic cerebral arteries. Ryanodine and thapsigargin inhibited Ca2+ sparks and Ca(2+)-dependent potassium (KCa) currents, suggesting that Ca2+ sparks activate KCa channels. Furthermore, KCa channels activated by Ca2+ sparks appeared to hyperpolarize and dilate pressurized myogenic arteries because ryanodine and thapsigargin depolarized and constricted these arteries to an extent similar to that produced by blockers of KCa channels. Ca2+ sparks indirectly cause vasodilation through activation of KCa channels, but have little direct effect on spatially averaged [Ca2+]i, which regulates contraction.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell reports
                2211-1247
                26 September 2020
                22 September 2020
                03 October 2020
                : 32
                : 12
                : 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
                NIHMS1631917
                10.1016/j.celrep.2020.108169
                7532726
                32966798

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

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                Cell biology

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