Clustering Properties of Neuronal Ryanodine Receptor 2 and Remodeling in the APP/PS1 Mouse Model of Alzheimer's...

The ryanodine receptor (RyR2) is an intracellular Ca²⁺ release channel which mediates numerous cellular functions across different tissues. Dysregulation of RyR2 channel activity leads to pathological Ca²⁺ release, which often underlies disrupted cellular signaling in disease states. In the heart, RyR2 channels forms discrete clusters and calcium release units (CRUs) which control channel activity. These structures demonstrate nanoscale remodeling in disease states associated with pathological Ca²⁺ release activity in the heart. Hence, these nanoscale structures are critical in regulating Ca²⁺ release in health and disease. RyR2 is also expressed in brain; however, whether analogous clusters and CRUs form in neurons remains unexplored.

Using super-resolution imaging, we assessed RyR2 organization in CA1 pyramidal neurons of wild-type mice. Furthermore, we used the APP/PS1 mouse model of Alzheimer's disease (AD) to assess whether there is nanoscale remodeling of RyR2 in a setting associated with pathological Ca²⁺ release in neurons.

Here, we provide the first identification and detailed characterization of RyR2 clusters in central nervous system neurons, which are comparable to those reported in the heart. Moreover, we observed a decrease in RyR2 cluster size and reduced CRU organization in AD mice at an age associated with high plaque burden and cognitive deficits. This remodeling is analogous to that reported in pathological states in the heart.

Together, these findings implicate the nanoscale remodeling of RyR2 clusters and CRUs as a novel mechanism underlying Ca²⁺ channel dysregulation and neuronal dysfunction in AD.