Abstract
Alzheimer’s disease (AD) is the most common form of dementia. Despite the amyloid beta hypothesis dominating the field, no research has been able to produce a widely accepted successful therapy for >20 years. A growing body of evidence associates the intracellular calcium release channel, ryanodine receptor (RyR2), with AD progression. In the heart, it is well known that RyR2 function is regulated through its ultrastructural arrangement, with RyR2 forming discrete clusters. The size and structure of these clusters impacts the activity of RyR2, with distinctive fragmentation of clusters associated with pathological calcium leak. Whether a similar clustering of RyR2 occurs in neurons and whether changes in clustering underlies the altered calcium release in AD has never been examined. Here super-resolution microscopy (dSTORM) was used to analyze the structure of RyR2 clusters in the soma and dendrites of hippocampal CA1 neurons from wild-type and AD model (APPswe/PS1ΔE9) mouse brains as well as a hippocampal culture model of AD (Aβ1-42 treatment). The results show a clear formation of RyR2 clusters in hippocampal neurons, confirming that similar structures are formed in the heart and brain. Excitingly, the data obtained from brain slices indicate that RyR2 clusters become smaller in AD mice, however this was not reproduced in the neuronal culture model. However, differences in the structure of RyR2 clusters were observed between brain slices and cell culture; suggesting the cell culture model might not be appropriate to study change in RyR2 clustering in AD. Overall, these results demonstrate the novel findings of (1) RyR2 cluster formation in hippocampal neurons, and (2) that these clusters remodel in AD.