Normalizing neuronal function in Alzheimer's disease using calcium channel blockers
Targeting aberrant calcium signaling for Alzheimer's Disease therapeutics
The broad question this project is designed to address is what is the functional relationship between calcium dysregulation in Alzheimer's disease and the hallmark features of the disease. As a breakdown in synaptic function and structure is correlated most highly with cognitive loss, this aspect will be a significant focus. If Ryanodine receptor (RyR)-mediated calcium release is intimately involved in Alzheimer's disease pathogenesis in both early and late stages, then manipulating RYR ion channel function should offer both novel therapeutic strategies, and, a better understanding of the disease process itself.
Overall, this project is designed to address the functional relationship between aberrant neuronal signaling known to exist in certain forms of Alzheimer's disease and the later hallmark features of the disease, including memory loss. A breakdown in how neurons communicate with each other correlates most highly with this cognitive loss, but how this occurs is unclear. It is likely that well-characterized alterations in neuronal calcium signaling may underlie the deficits in neuronal function and communication. Therefore, this aspect will be a significant focus. If intracellular calcium dysregulation is intimately involved in Alzheimer's disease pathogenesis at both early and late stages, then targeting and manipulating specific calcium channels should offer both novel therapeutic strategies, and, a better understanding of the disease process itself. Using mouse models of Alzheimer's disease, I employ highly novel experimental approaches which allow me to image calcium signaling, record electrophysiological signals from individual neurons and measure synaptic communication between neurons in real time. This is in combination with measuring biochemical and molecular changes that occur in the Alzheimer's disease neurons. My previous studies have identified a particular calcium channel (the ryanodine receptor, RyR) that largely underlies a massive increase in calcium release at synapses, the key points of neuronal contact that are impaired in Alzheimer's disease. I have acquired a novel compound that can suppress calcium release from this channel and normalize the overall calcium response in neurons. The aims in this study will be to determine if normalizing this aberrant RyR activity can also return synaptic communication/transmission back to normalcy, retain the structural integrity of the synapse, and reduce the amyloid plaques and tau tangles. The effects on retaining cognitive function will also be tested.
These series of experiments are unique and highly innovative in that I am directly 'seeing' the communication deficits between neurons, both at the calcium signaling and electrochemical level, in the Alzheimer's disease mice. This is accomplished using a custom-built 2-photon imaging system in parallel with electrophysiological techniques. This is in combination with molecular and behavioral techniques. Therefore, I can observe the short and long term effects of normalizing this aberrant calcium signal in the Alzheimer's disease mice, at the cellular level as well as the cognitive/behavioral level.
Dr. Stutzmann’s team investigated whether reversing the abnormal calcium responses at early stages of Alzheimer’s disease (AD) can prevent or reduce further damage. The team demonstrated that targeting calcium channels underlying the nerve signaling abnormalities is a novel approach to prevent the progression of AD. To accomplish this, they normalized the calcium levels released from the endoplasmic reticulum (an organelle with high calcium store levels, and is also important in protein folding) by delivering ryanodine receptor (RyR, a calcium channel on the ER) stabilizing drugs to mice engineered to have AD. The team found that treatment with RyR stabilizers restored a broad range of abnormal brain events that are linked to AD and cognitive impairment, including calcium dysregulation, synaptic transmission and plasticity (nerve cell communication) deficits, and beta amyloid deposition. These results validate the role of early calcium dysregulation in AD and establish its link with synaptic pathology and accelerated amyloid deposition, and therefore, serve as a “proof of principle” for exploring novel ER-targeted therapeutic approaches for the treatment and prevention of AD.
First published on: April 6, 2010
Last modified on: March 22, 2013