Targeting Post-Translational Remodeling of Ryanodine Receptor: A New Track for Alzheimer's Disease Therapy?

Pathologic calcium (Ca2+) signaling linked to Alzheimer's Disease (AD) involves the intracellular Ca2+ release channels/ryanodine receptors (RyRs). RyRs are macromolecular complexes where the protein-protein interactions between RyRs and several regulatory proteins impact the channel function. Pharmacological and genetic approaches link the destabilization of RyRs macromolecular complexes to several human pathologies including brain disorders. In this review, we discuss our recent data, which demonstrated that enhanced neuronal RyR2-mediated Ca2+ leak in AD is associated with posttranslational modifications (hyperphosphorylation, oxidation, and nitrosylation) leading to RyR2 macromolecular complex remodeling, and dissociation of the stabilizing protein Calstabin2 from the channel. We describe RyR macromolecular complex structure and discuss the molecular mechanisms and signaling cascade underlying neuronal RyR2 remodeling in AD. We provide evidence linking RyR2 dysfunction with β-adrenergic signaling cascade that is altered in AD. RyR2 remodeling in AD leads to histopathological lesions, alteration of synaptic plasticity, learning and memory deficits. Targeting RyR macromolecular complex remodeling should be considered as a new therapeutic window to treat/or prevent AD setting and/or progression.