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

Abstract

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.

Ca2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease

“…In addition, the membrane afterhyperpolarization mediated by activation of postsynaptic Ca 2+ activated SK2 channels is increased in a 3xTg AD mouse model [ 46 ], leading to decreased postsynaptic membrane excitability and possible decreased synaptic transmission. It should also be noted that the decreased hippocampal synaptic transmission recently observed in a 5xTg AD mouse model was coupled with increased postsynaptic membrane excitability, due to an RyR2 mediated decrease in A-type K + current (I A ) [ 47 ], thus further illustrating the complexity of synaptic effects observed in AD mouse models. It is also noteworthy that the in vivo hyperexcitability studies mentioned above were conducted in animals anesthetized using the volatile inhalational anesthetic isoflurane.…”

“…The RyR modulator dantrolene (Ryanodex) is an FDA approved medication that has been shown to be effective in reversing many of the synaptic and cognitive effects seen in mouse models of AD [ 8 , 114 , 115 , 116 ], and has good CNS penetration when given orally or by nasal administration [ 117 ]. In addition, the clinically used L-type VGCC inhibitor isradipine has been shown to be neuroprotective in an AD mouse model [ 22 ], as has the beta-blocker carvedilol [ 47 ], however results from a recent large clinical study suggested no benefit of the VGCC antagonist nilvadipine as a treatment for AD [ 118 ]. Although the failure of large scale clinical trials for VGCC inhibitors as a treatment for AD has resulted in diminished enthusiasm for their use, the antiepileptic drug levetiracetam, which inhibits presynaptic VGCCs [ 68 ], has been shown to be beneficial in AD patients [ 69 ] and clinical trials for its use in the treatment of AD are ongoing [ 119 ].…”

“…RyR expression and RyR mediated Ca 2+ responses are increased in the soma and dendritic spines of hippocampal and cortical pyramidal neurons of AD mice expressing PS1 mutations ( Figure 1 and Figure 2 ) [ 9 , 30 , 127 ], effects which are normalized by acute or chronic treatment with dantrolene, a negative allosteric RyR modulator [ 50 , 114 ]. In particular, the RyR2 isoform, which is overexpressed in the hippocampus of AD mice [ 30 , 114 ], plays an important role in maintenance of synaptic function [ 128 ] and shortening of the RyR2 mean channel open time reverses the synaptic dysfunction and Ca 2+ dyshomeostasis observed in an AD mouse model [ 47 ]. Human-induced neurons (HiN) derived from fibroblasts from AD patients expressing the PS1 mutation also display increased RyR expression and evoked RyR Ca 2+ release [ 53 ], and RyR expression is also increased in post-mortem brains of AD patients, and patients with mild cognitive impairment [ 129 , 130 ].…”

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer’s Pathogenesis—And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder

“…Knockout of p47, an obligate component of the NOX2-dependent NADPH oxidase complex, has recently been shown to prevent cognitive dysfunction and tau hyperphosphorylation in two types of AD mouse models without significantly impacting soluble or insoluble amyloid β levels [ 19 ]. When mice are genetically modified to express modified forms of the RYR2 calcium channel that have reduced open times, cognitive function is likewise preserved in AD model mice; administration of the R-isoform of the drug carvedilol, which similarly down-regulates RYR2 open time, without blocking its opening, is similarly protective [ 20 ]. Genetically up-regulated expression of the mitochondrial Na-Ca exchanger preserves cognitive function in AD model mice, demonstrating a crucial role for mitochondrial calcium overload in AD [ 21 ].…”

RyR2 disease mutations at the C-terminal domain intersubunit interface alter closed-state stability and channel activation

“…It plays an essential role in excitation–contraction coupling by controlling the release of Ca 2+ from the SR into the cytoplasm ( 1 , 2 , 3 , 4 , 5 ). RyR2 is also abundantly expressed in the brain and critically involved in learning and memory ( 6 , 7 , 8 , 9 ). Because of its important physiological roles, mutations in RyR2 can cause cardiac arrhythmias, cardiomyopathies, and neuronal disorders ( 4 , 10 , 11 , 12 , 13 ).…”