‘Alzheimer’s in a Dish’ Expected To Hasten Drug Development

Currently taking the science world by storm are Harvard neuroscientist Rudolph E. Tanzi, PhD, a past recipient of several BrightFocus grants, and 2013-15 BrightFocus Grantee Se Hoon Choi, PhD, both based at the Genetics and Aging Research Unit of Massachusetts General Hospital, which Tanzi directs. These researchers and their colleagues have managed to accomplish what no one has done before. They grew human brain cells in a petri dish using a gel culture, and then infiltrated them with genes that encode for amyloid precursor protein and presenilin1, both of which were earlier discoveries in Tanzi’s lab and are associated with the most robustly inheritable, early-onset familial forms of Alzheimer’s disease.

Published online October 13 in the journal Nature (Choi et al, 2014), their newest discovery is being hailed a “game changer” for Alzheimer’s research by a number of major news outlets, including The New York Times, Time, Newsweek, and the Boston Globe. That’s because experts predict the ‘Alzheimer’s in a dish’ method will supplement the mouse model currently used for studying Alzheimer’s, and make it possible to test potentially thousands of new drugs for Alzheimer’s much more rapidly, and at a lower cost.

Currently it takes up to a year for mouse models of the disease to develop the signature plaques and tangles of Alzheimer’s, whereas in the petri dish, brittle plaques resembling steel wool and neurofibrillary tangles begin to develop a few weeks after Alzheimer’s genes are introduced. The gain in speed and efficiency will make it possible to test new drug compounds in a fraction of the time and an estimated one-tenth of the cost of that using mice.

There’s still another advantage to “Alzheimer’s in a dish,” in that it has helped researchers sort out the respective roles that beta amyloid plaques and tau tangles play in the disease process. Using the mouse model, scientists are able to reproduce beta amyloid plaques, but not tau tangles. This shortcoming limited the ability to test compounds targeting tau, and also contributed to uncertainty over the exact course of disease progression. Both proteins, beta amyloid and tau, are present in the normal brain, and it has been speculated that the Alzheimer’s brain undergoes a conversion where something—overproduction, changes in enzyme coding, or lack of clearance—triggers beta amyloid and tau to collect in abnormal concentrations.

The end result is only too well known—beta amyloid and tau proteins “aggregate” or clump together and form the lethal plaques and tangles that stifle neuronal function. However, what hasn’t been known is whether amyloid plaques trigger the formation of tau tangles, or whether tau causes beta amyloid deposits to become stickier and bunch together, thus killing neurons.

After watching Alzheimer’s disease progress in their new petri dish model, Tanzi and colleagues have affirmed that the disease process begins with beta amyloid overproduction, followed by the formation of tau tangles. Their observations were confirmed in experiments where, after blocking the formation of beta amyloid with a known inhibitor, tau tangles never formed.

Another scientist, George Glenner, had advanced the idea that amyloid accumulation drives Alzheimer’s and other forms of dementia, and published those finding in 1984. Unfortunately, Glenner himself died from amyloidosis—caused by lethal overproduction of a form of the protein he had characterized—in 1995, at age 67. Of approximately 60 amyloid proteins that have been identified, at least 36 have been associated with a human disease.

“This is how the disease starts,” Tanzi told The New York Times, “but for 30 years ago there was no proof that amyloid drives the rest of the disease.”

Tanzi, a four-time BrightFocus grant recipient, had in earlier BrightFocus-supported research focused on discovering gene variants that increase a person’s Alzheimer’s risk and are associated with changes in protein expression that might prove to be therapeutic targets. As such, he is wasting no time in putting “Alzheimer’s in a dish” to work. He’s now embarking on a project to test 1,200 drugs on the market and 5,000 experimental Alzheimer’s drugs that have made it through the first phase of clinical testing (ie, safety testing). The next steps are to evaluate dosing and effectiveness, and hopefully the petri dish approach will narrow the field to only the most promising candidates. To attempt this type of wholescale screening of potentially useful drug compounds in mouse studies would be prohibitive.

To hasten the drug pipeline, BrightFocus is funding other research into potential disease-modifying targets and therapeutic approaches against Alzheimer’s, as well as screening techniques that might shorten the time it takes to investigate new compounds. An example is the work being done by David Brody, MD, PhD, at Washington University in St. Louis (WUSL), who is developing a very rapid technology for monitoring a drug’s interaction with amyloid in a way that does not require living cells.

“It’s possible that several of these methods, once validated, will converge scientifically,” commented BrightFocus VP of Scientific Affairs Guy Eakin, PhD. “Screening might begin with a rapid analysis of interactions between a potential compound and beta amyloid, followed by testing in a cell, followed by studies in better animal models, and moving into more streamlined human clinical trials.”

Ultimately, “all of these will work together to reduce drug development time,” Eakin said.

In Tanzi’s case, he and his fellow researchers attribute their “Alzheimer’s in a dish” breakthrough to their ingenious approach to growing human neurons in a three-dimensional medium, or gel, which resembles the way neurons are suspended in the brain. However, experts reacting to the story have pointed out that cells living in a petri dish lack various components of the brain, such as immune cells, which appear to interact with and possibly contribute to Alzheimer’s changes, as well as blood vessels and other cell types that may affect the disease process. Another limitation is that in order to develop Alzheimer’s disease very quickly, the petri dish model relies on genes from early onset Alzheimer’s, so if there are differences in late onset and early onset disease, this method may not develop them.

In these ways—and possibly more will emerge—the mouse model is likely to remain indispensable in Alzheimer’s research as a way of studying how the disease process unfolds over time and gaining a better understanding of how different biological mechanisms may possibly interact.