RyR2-dependent modulation of neuronal hyperactivity: A potential therapeutic target for treating Alzheimer's disease

Increasing evidence suggests that simply reducing beta-amyloid (A beta) 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 A beta-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. By 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.