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.
Keywords: Ryanodine receptor, Calcium, Alzheimer’s disease, Amyloid Precursor Protein, Post-translational modifications,
β2-adrenergic signaling, Protein Kinase A, Reactive oxygen species, Nitrosative oxygen species, Amyloid β.
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