Limiting RyR2 open time prevents Alzheimer's disease‐related deficits in the 3xTG‐AD mouse model

Abstract

Increasing evidence suggests that Alzheimer's disease (AD) progression is driven by a vicious cycle of soluble β‐amyloid (Aβ)‐induced neuronal hyperactivity. Thus, breaking this vicious cycle by suppressing neuronal hyperactivity may represent a logical approach to stopping AD progression. In support of this, we have recently shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevented neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in a rapid, early onset AD mouse model (5xFAD). Here, we assessed the impact of limiting RyR2 open time on AD‐related deficits in a relatively late occurring, slow developing AD mouse model (3xTG‐AD) that bears more resemblance (compared to 5xFAD) to that of human AD. Using behavioral tests, long‐term potentiation recordings, and Golgi and Nissl staining, we found that the RyR2‐E4872Q mutation, which markedly shortens the open duration of the RyR2 channel, prevented learning and memory impairment, defective long‐term potentiation, dendritic spine loss, and neuronal cell death in the 3xTG‐AD mice. Furthermore, pharmacologically shortening the RyR2 open time with R‐carvedilol rescued these AD‐related deficits in 3xTG mice. Therefore, limiting RyR2 open time may offer a promising, neuronal hyperactivity‐targeted anti‐AD strategy.

Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease–causing gene mutations

“…Po are currently unknown. Based on our present and previous studies, 22,43,44 we propose that increased RyR2 Po may enhance the neuronal excitability of hippocampal CA1 neurons by reducing the A-type K + current. Reduced A-type K + current would lead to neuronal hyperactivity, which would result in overactivation of surface Ca 2+ channels and abnormal elevation of cytosol and/or endoplasmic reticulum (ER) Ca 2+ levels.…”

“…The mechanisms by which However, the challenge is how to control the extent of reduction in RyR2 expression, as overly reduced RyR2 expression itself can lead to detrimental impact on neuronal function. We have recently shown that genetically and pharmacologically limiting the open time of RyR2 prevented and rescued AD-related deficits in mouse models of AD 22,43,44. Therefore, controlling the open time, rather than blocking the function and expression of RyR2, may represent a safer approach to suppressing overactive RyR2.…”

R-carvedilol, a potential new therapy for Alzheimer’s disease

“…However, this fast onset of AD pathology in 5xFAD mice is very different from that in human AD (Lee and Han, 2013;Jankowsky and Zheng, 2017). To determine whether R-carvedilol can also prevent and rescue cognitive decline in a mouse model whose AD progression is relatively slower than the 5xFAD mouse, Liu et al (2021), employed the well-known 3xTG AD mouse model, which is also widely used in AD studies, but the onset of AD symptoms is relatively late (Oddo et al, 2003;Jankowsky and Zheng, 2017). 3xTG +/mice (12-15 months old) were treated with R-carvedilol or DMSO for one month and behavioral tests and LTP measurements were conducted.…”

“…The clinically used carvedilol is a racemic mixture of ß-blocking S-carvedilol and non-β-blocking R-carvedilol (Bristow et al, 1996;Frishman, 1998;Zhou et al, 2011;Zhang et al, 2015). Recently, it has been shown that R-carvedilol alone prevented and rescued neuronal hyperactivity, memory impairment, and neuron loss without affecting the accumulation of ß-amyloid (Aβ) in mouse models of familial AD (FAD) in vivo and in vitro (Yao et al, 2020;Liu et al, 2021;Sun et al, 2021). This mini-review will discuss the potential application of R-Carvedilol as a new therapeutic strategy to treat AD.…”

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

“…Very recently, it has been demonstrated that increased RyR2 open probability induces neuronal hyperactivity and memory loss, two common manifestations of AD and AD progression [ 56 ]. Moreover, pharmacological treatment aimed to reduce RyR2 open time has been demonstrated to rescue AD-related deficits in mouse models, suggesting this molecular pathway as a potential target for addressing AD [ 57 ]. Among the “not in common” (son-specific) variants, we found a missense variant in the USP24 gene (PARK10), which encodes for a deubiquitinating enzyme, involved in protein turnover and degradation.…”