Statement of the Problem: A shared aspect among many neurodegenerative disorders is a limited understanding of cellular disease mechanisms. In our research, we have found that dysregulated calcium channels play a central and early role in driving diseases such as Alzheimer’s, Huntington’s and brain injury. Specifically, defects in intracellular calcium stores within the endoplasmic reticulum (ER) and their resident release channels such as the ryanodine receptor (RyR) are upstream of the major disease features such as protein aggregates and synaptic deficits. By focusing upon the proximal calcium channelopathy, rather than later-stage features, significant advances in understanding disease etiology may be made
Methodology & Theoretical Orientation: Whole cell patch clamp electrophysiology combined with 2-photon calcium imaging are used to record signaling from hippocampal neurons in acute brain slices from mouse models of Alzheimer’s disease (AD) and human neurons transformed from AD patients. Immunoassays and qRT PCR probe protein and transcript levels in mouse and human neurons.
Findings: In early stage AD mice, RyR-evoked calcium signals are significantly greater than non-transgenic controls, while calcium signaling though voltage-gated channels and NMDA receptors are not different. Similar observations were made in human neurons from AD patients. Additionally, RyR 2 message is increased in both the mouse and human AD neurons. Pharmacologically normalizing RyR-calcium release restores RyR2 levels in mice, as well as reduces many of the AD features including beta amyloid, hyperphosphorylated tau and synaptic loss.
Conclusion & Significance: Dysregulated ER calcium channel functioning is an early feature of AD in mouse models and human samples and likely initiates a pathogenic cascade in the proximal disease stages. Because of the multiple and essential roles of calcium signaling in neurons, alterations in RyRchannel properties can generate multiple downstream maladaptive effects such as those seen in neurodegenerative disorders.
