Targeting calcium channels as a novel therapeutic strategy for Alzheimer's disease: Preventing pathology from molecular to network levels

Abstract

An early pathogenic mechanism that affects all the major features and cognitive deficits associated with AD is dysregulated intracellular calcium signaling. In particular, ryanodine-receptor (RyR) mediated calcium is markedly increased in spines and synaptic compartments, and likely plays a proximal role in synaptic pathophysiology. Conversely, preventing the exaggerated calcium responses generated from intracellular stores may be a novel and effective therapeutic strategy for AD. Using a combination of approaches in AD mouse models (3xTg-AD, APP/PS1, and TgCRND8), including 2-photon calcium imaging and whole cell patch clamp recordings in hippocampal neurons, EM and confocal microscopy, and synaptic physiology to measure plasticity in local circuits and hippocampal networks, we tested the effects of existing and novel RyR modulators that will stabilize intracellular calcium signaling in neurons from AD mice. In presymptomatic and symptomatic AD mice, sub-chronic treatment with RyR-targeted compounds prevented a broad range of AD-related symptoms, including aberrant calcium signaling, synaptic transmission and plasticity deficits, structural impairments at the synaptic and ultrastructural levels, amyloid and tau histopathology, and molecular alterations in RyR expression levels. Stabilizing the RyR-evoked calcium responses in AD mouse models was effective in preventing a broad range of neuropathological features associated with AD. The breadth of targets affected by this approach likely reflects the upstream and central role that dysregulated calcium plays in the overall disease process. Thus, a RyR-targeted strategy may provide the needed combinatorial algorithm to prevent the multifaceted pathological progression of AD.