The new mantra for researchers fighting Alzheimer’s disease is “go early,” before memory loss or other pathology appears. The rationale for this approach holds that by the time dementia sets in the disease may already be destroying brain cells, placing severe limits on treatment options.
Some large clinical trials are now testing drugs intended to clear up the brain’s cellular detritus—the aggregations of amyloid and tau proteins that may ultimately destroy brain cells. So far this approach has had decidedly mixed results.
Some researchers are choosing a different direction. They have begun to ask what happens in the brain before the plaques and tangles of amyloid and tau appear—and to look at interventions that might work at this incipient disease stage.
The Alzheimer’s Drug Discovery Foundation has focused in recent years on funding new agents that do not target amyloid but are intended to address other manifestations of the disease, such as inflammation and the energy metabolism of neurons.
At a foundation meeting last month in Jersey City, N.J., neuroscientist Grace Stutzmann of the Chicago Medical School at Rosalind Franklin University of Medicine and Science presented her work on restoring a basic cellular process—called calcium signaling—that goes off track in Alzheimer’s. Scientific American asked her recently about her work.
[An edited transcript of the conversation follows.]
Scientific American: Can you explain in a simple manner for our readers what calcium signaling is in the brain and what can go wrong in Alzheimer's?
While many people are aware of calcium as a component of strong bones, calcium is also a very important feature of cellular function. Calcium ions within brain cells play fundamental roles in activating genes to make proteins in energy metabolism, in signaling inside cells and even in cell death. Perhaps most relevant to Alzheimer’s disease though is its central role in neuronal transmission and communication between synapses (junctions between neurons). These are the cellular mechanisms by which memories are formed and maintained. In Alzheimer’s disease, too much calcium is being released within the neuron, and this initiates or accelerates many of the pathological processes seen in Alzheimer’s disease (AD), especially the events that lead to memory loss.
Is stopping the process of aberrant calcium signaling a good place to intervene? Is that because of the particular stage at which calcium becomes a problem in the course of the disease?
The dysregulated calcium signaling is thought to occur early in the disease process, which suggests it is part of the “cause” rather than a later-stage “effect.” Mechanistically, this supports targeting calcium abnormalities as a good therapeutic strategy. Importantly, we feel that our laboratory has identified the particular channel underlying the excess calcium release (the ryanodine receptor), which provides a specific target when trying to prevent the calcium dysregulation.
Can you explain specifically what you’ve done?
We first confirmed the role of the specific calcium channel in AD by examining its effects in several experimental models of AD, and we also confirmed abnormalities in human brains from AD patients. We then moved back to the models (including mice genetically engineered to exhibit AD pathology) and tested existing drugs known to inhibit the calcium channel, which generated incredibly encouraging results. Not only did one of these drugs reverse the excess amounts of calcium but it also altered many of the other aspects of AD, such as the accumulation of amyloid and tau, loss of synapses, and impaired synaptic plasticity. These findings set the stage for the development of our own compounds that are designed for better targeting of the receptors and gaining better access to the brain. We soon partnered with a medicinal chemistry group to help design and synthesize a series of new compounds to test in these models systems of AD.
How will you test people without symptoms to know whether they're at risk?
Ah, there is the rub. Numerous groups, ours included, are looking for biomarkers to indicate amount of risk or likelihood of developing AD. And there is also brain imaging of plaques (and more recently tau pathology) that many are using as an indicator of AD risk. But since there is little correlation between plaques and cognitive function, many of us are questioning this as a diagnostic or biomarker tool. So for now it's very hard to accurately assess risk in most people. Realistically, we are hoping to catch early-stage symptoms including the behavioral and memory disruptions, and then prevent further cognitive impairment.
Tell us about the company you've started and the drug you're developing.
Once we realized we had a valid and novel strategy to treat AD, a library of new compounds and powerful biological screening assays to test our compounds, we got to work trying to identify which of these compounds could prove to be effective in treating AD. To our great joy, the first generation of compounds produced several successful “hits,” which restored intracellular calcium signaling to its normal state in the AD models, and also reduced several of the related pathological features of AD.
Soon after, we partnered with SmartHealth, a North Chicago-based health care activator (an incubator for biotech startups), to create NeuroLucent to accelerate the process of developing, testing and optimizing our new compounds to hopefully move them into the clinic. Glenn Gottfried, an adviser with SmartHealth, is serving as president. I also brought in a medicinal chemist, Dr. John Buolamwini, and a molecular biologist, Dr. Robert Marr, both colleagues with me at Rosalind Franklin University. We’re still a new startup, but we are in the process of raising funds and establishing partnerships to scale up and advance the complex process of moving a compound from the lab to the FDA.
Haven't there been previous attempts to try to correct calcium signaling? How is yours different?
That is correct. This is not the first calcium-channel strategy attempted for the treatment of AD. However, the previous approaches were targeting entirely different types of calcium channels, found on the outer membrane of the cell, that do not seem to be linked to AD pathology in any clear way. For example, there is a class of calcium channels on the surface of the cells that is activated by excitatory activity that opens the cell channel. Drugs that inhibit these calcium channels have been very effective for several conditions, such as high blood pressure, but did not improve cognition or reduce the symptoms of AD. We have also been studying these channels in our experimental models of AD, and they have always functioned normally. Since this series of calcium channels doesn’t seem to be defective or causative in AD, I can understand why these previous attempts weren’t successful in the clinic.
A major difference in our approach is that the calcium channel we are targeting is found inside the cell, and controls calcium signaling from the endoplasmic reticulum (ER), a cell component with a very high calcium concentration. In AD, the channel on the ER membrane releases too much calcium from its internal stores, and this triggers a host of pathological cascades. We are attempting to normalize the calcium signaling through ER channels and target this one specific source. This is mechanistically much different than the previous attempts. Plus, we know in experimental AD models and in human AD patients that this calcium source is functioning abnormally. Several research labs have demonstrated this across many different models. If it were only our lab obtaining these findings, I wouldn’t feel comfortable trusting our results in isolation.
Is it important to consider your approach given the poor track record with other Alzheimer's drugs?
I do feel very strongly about this, and it doesn’t have to be “my” approach per se—but anymechanistically valid approach that is distinct from the series of recent failed clinical trials. The majority of the compounds that disappointed were targeting a particular protein aggregate, beta-amyloid plaques. And, while the presence of plaques is integral to the diagnosis of AD, it is unclear what their role is in the disease process and how the accumulation of beta-amyloid actually links to memory loss. Actually, several of these drugs worked very well in that they were able to reduce the beta amyloid in the brain; however, they were not able to show any improvement in cognitive function.
In parallel, we know there is little relationship between the amount of amyloid in one’s brain and your memory function. In fact, those “super-agers”—your 95-year-old great-great-aunt who finishes the crossword puzzle in 20 minutes, is president of the bridge club and has a better golf handicap than you—may have just as many amyloid plaques in her brain as AD patients. In the big picture, I think we need to take a few giant steps backwards and work on understanding the early mechanisms of AD as it relates to memory loss. That will then enable us to build therapeutic strategies based on these data. We feel enormous potential exists in addressing an early and central signaling pathway that affects amyloid production, tau pathology, neuroinflammation and memory loss, among other AD features, but there may be other targets besides calcium dysregulation that would be effective. I think the research community needs to increase our efforts in finding the common denominator driving the multifaceted disease processes in AD. Our lab is continuing to explore what is causing AD and now is using human neurons to validate our approach. But as a field, we research scientists need to better understand what it is we are fighting in order to formulate the best approach.
Update: The name of the Alzheimer's Drug Discovery Foundation has been corrected.