RyR2-dependent modulation of neuronal hyperactivity, a potential therapeutic target for treating alzheimer's disease.

Increasing evidence suggests that simply reducing β-amyloid (Aβ) plaques may not significantly affect the progression of Alzheimer's Disease (AD). There is also increasing evidence indicating that AD progression is driven by a vicious cycle of soluble Aβ-induced neuronal hyperactivity. In support of this, it has recently been shown that genetically and pharmacologically limiting ryanodine receptor 2 (RyR2) open time prevents neuronal hyperactivity, memory impairment, dendritic spine loss, and neuronal cell death in AD mouse models. In contrast, increased RyR2 open probability (Po) exacerbates the onset of familial AD-associated neuronal dysfunction and induces AD-like defects in the absence of AD-causing gene mutations. Thus, RyR2-dependent modulation of neuronal hyperactivity represents a promising new target for combating AD. Abstract figure legend An increasing body of evidence indicates that upregulated neuronal activity, diminished LTP, and impaired learning and memory are primary early deficits in Alzheimer's disease (AD) animal models and humans. Interestingly, a mouse model expressing a ryanodine receptor 2 (RyR2) mutation R4496C +/- that enhances the open probability of the RyR2 channel displays the same defects found in early stages of AD, whereas genetically and pharmacologically limiting RyR2 open time prevents neuronal hyperactivity, LTP deficit, memory impairment, dendritic spine loss, and neuronal cell death in AD mouse models. Therefore, RyR2-dependent modulation of neuronal hyperactivity represents a promising new target for combating AD. This article is protected by copyright. All rights reserved.