Grace E Stutzmann
The Chicago Medical School - Rosalind Franklin University, USA
Title: Calcium signaling in the CNS in health and neurodegenerative disease
Biography
Biography: Grace E Stutzmann
Abstract
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. Specifi cally, 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 defi cits. By focusing upon the proximal calcium channelopathy,
rather than later-stage features, signifi cant advances in understanding disease etiology may be made.
Methodology & Th eoretical 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 signifi cantly greater than non-transgenic controls, while
calcium signaling though voltage-gated channels and NMDA receptors are not diff erent. 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 RyR 2 levels in mice, as well as reduces many of the AD features
including beta amyloid, hyperphosphorylated tau and synaptic loss.
Conclusion & Signifi cance: 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 RyR-channel properties can generate multiple downstream maladaptive
eff ects such as those seen in neurodegenerative disorders.