A team led by Cure Alzheimer’s Fund Research Consortium Chair Rudy Tanzi, Ph.D., has, for the first time created ‘Alzheimer’s in a dish’ – a combination of both amyloid and tau pathology in human nerve cells living inside a Petri dish.
In September the journal Nature published a study led by Dr. Tanzi that for the first time induced the creation of both key aspects of Alzheimer’s pathologies – amyloid plaques and tau tangles – in human nerve cells with a known Alzheimer’s gene mutation. These nerve cells had been developed first from human stem cells. “In summary, we have successfully recapitulated Abeta and tau pathology in a single 3-D human neural cell culture system for the first time,” wrote Tanzi and fellow researchers in the magazine. Further, the group reported it was able to inhibit both Abeta and tau. “This is a big deal,” Tanzi says. “It creates a near-ideal lab model of the disease that will help us dramatically accelerate the process of drug testing.
A promising first-in-class drug stimulates the creation of new nerve cells in the brains of Alzheimer's mice and will soon be tested in the brains of human patients, thanks to new research by Dr. Sam Gandy, member of Cure Alzheimer's Fund's Research Consortium, at Mount Sinai School of Medicine in New York.
A new article by Gandy's team just published in the journal Molecular Psychiatry outlines the extraordinary promise of the drug, known as a "mGluR2/3 blocker". Created by the Japanese pharmaceutical firm Taisho and originally studied for depression, the drug acts by stimulating stem cells in the hippocampus to divide and form new nerve cells. What's more, the learning behavior of the Alzheimer's mice being treated with the mGluR2/3 blocker has been sustained at its normal level, in contrast to the steady decline of the mice not being treated.
mGluR2/3 originally caught the attention of Gandy and his team for its possible ability to inhibit production of the toxic protein Abeta42, which is associated with Alzheimer's disease. With funding from Cure Alzheimer's Fund, they conducted a pilot study of the drug's effects on a particular strain of mice. That study turned out such promising results that it has drawn $1 million in funding from the Veterans Administration "MERIT Review" program that supports Gandy's lab at the James J Peters VA Medical Center in the Bronx.
The mGluR2/3 blocker has also been administered to healthy young human subjects, and so far has been shown to be safe. The next step for Gandy's team will be to treat elderly human subjects with the drug to test safety in this population before gearing up to test the drug in Alzheimer's disease. With the focus of mainstream Alzheimer's research turning toward prevention, the mGluR2/3 blocker is one of the few drugs that holds promise for repairing brains already damaged by neurodegenerative disease.
All of these efforts proceed from the international Stem Cell Consortium formed by Gandy in 2012 and funded by Cure Alzheimer's Fund. "It's extraordinary that in such a short time, we have moved from ordinary skin cells to induced pluripotent stem cells in a petri dish, to lab-generated human nerve cells, and now to a drug that could potentially create those cells inside a human brain," said Gandy. "We realize that we are unlikely to have much impact in late-stage Alzheimer's, but we are cautiously hopeful that this drug might arrest Alzheimer's disease at an early stage so that patients can remain functional for more extended periods." Gandy's mGluR2/3 blocker is one of five brain cell regenerating agents currently undergoing testing in labs around the world.
"We are so proud of this development," said Cure Alzheimer's chairman Jeffrey Morby. "Helping incubate cutting edge science that can gain momentum with federal funding -- this is precisely why Cure Alzheimer's Fund exists."
The world already is very familiar with both Alzheimer’s disease (AD), primarily a disease that occurs in the elderly, and Down syndrome (DS), a genetic condition present at birth. What many don’t realize is that these two conditions also overlap. By age 40, nearly all people born with Down syndrome have begun accruing the plaque and tangle hallmarks of Alzheimer’s. By age 60, most exhibit signs of dementia.
Why does this happen? The culprit is genetic. Humans have 23 chromosomes; Down syndrome, also known as “Trisomy 21,” is caused by the overproduction of chromosome 21 during the development of the egg, sperm or embryo. Instead of the usual two copies (one from mom, the other from dad), children with Down syndrome are born with three copies of chromosome 21 in every cell. This additional chromosome is responsible for the overproduction of various proteins—including those that cause the plaques and tangles behind Alzheimer’s.
The AD-DS connection
Focusing on this intriguing AD-DS connection, Cure Alzheimer’s Fund’s Rudy Tanzi, Ph.D., was one of three researchers in 1986 to discover the first-known Alzheimer’s gene, known as Alzheimer’s Precursor Protein (APP), located on chromosome 21. This discovery helped usher in a new era of Alzheimer’s genetic research. Since then, researchers have continued studying the AD-DS connection for further clues about the precise mechanisms of both diseases.
Since 2013, Cure Alzheimer’s Fund has been supporting research by the distinguished neuroscientist and Down syndrome expert William Mobley, M.D., Ph.D., whose lab is based at the University of California, San Diego. Mobley is part of a team working to exploit a hypothesis that inhibiting a protein called monoacylglycerol lipase (MAGL)—which gets overproduced in people with Down syndrome—will, in turn, reduce the production of Abeta and, subsequently, Alzheimer’s neuropathology.
Mobley, who recently joined the Scientific Advisory Board of Cure Alzheimer’s Fund (CAF), is working with fellow researcher Alexander Kleschevnikov, Ph.D., to develop therapeutic techniques for inhibiting MAGL; this work is being done in collaboration with Abide Therapeutics. Based in San Diego, Abide specializes in developing drugs connected to a class of enzymes called serine hydrolases, which play an important role in regulating central nervous system signaling as well as digestion, metabolism, inflammation, blood clotting and the life cycle of pathogens.
“We are extremely grateful to the Cure Alzheimer’s Fund for supporting this project,” said Mobley after the CAF grant last year, “which has the potential to benefit persons with Down syndrome and, if successful, will have a direct application to patients with Alzheimer’s disease.”
One step closer
“This is a terrific example of a ‘cross-platform’ project that we’re especially proud to support,” said Tim Armour, president and CEO of Cure Alzheimer’s Fund. “The results of Dr. Mobley’s work will undoubtedly help improve our understanding of both Alzheimer’s and Down syndrome.”
Help Us Continue This Research
Please help Cure Alzheimer's Fund continue to support important Alzheimer's research, like that being done in Dr. Mobley's lab, by making a donation today. Remember that 100% of all donations goes directly to research, since our Founders pay all of our overhead expenses.
At its core, Alzheimer’s is a disease that disrupts communications between neurons (nerve cells) in the brain, and ultimately kills those neurons. Cure Alzheimer’s Fund has committed to understanding this destructive process as a necessary component to stopping the disease. To that end, it has recruited four of the world’s top experts in the field: University of California, San Diego’s Roberto Malinow, Stanford’s Robert Malenka and Thomas Südhof, and Rick Huganir at Johns Hopkins.
The human brain contains 100 billion neurons, exchanging electrochemical signals with one another via 100 trillion connections called “synapses.” All human thought and action depends on the health of these synaptic connections. The destruction of synapses correlates very closely with the progressive symptoms of Alzheimer’s.
Growing evidence suggests that Abeta, one of the known culprits of Alzheimer’s, affects synapses early in the disease. At the University of California, San Diego, Roberto Malinow is exploring precisely how Abeta disrupts the mechanism of synapses, and whether preventing this disruption would save neurons. He also is investigating whether some particular feature of neuronal activity spurs the production of Abeta to begin with. Malinow holds the Shiley-Marcos Endowed Chair in Alzheimer’s Disease Research at UCSD.
Overseeing this work from Cure Alzheimer’s Scientific Advisory Board are Rob Malenka and Tom Südhof. Close collaborators at Stanford, Malenka and Südhof have elucidated the molecular mechanisms by which neural circuits are reorganized by experience. Together, they have laid the groundwork for a much more sophisticated understanding of the mechanisms by which neurons communicate and of the adaptations in synaptic communication, which underlie all forms of normal and pathological behavior. They currently are applying that breadth of expertise to the challenge of synaptic loss in Alzheimer’s.
“The guiding philosophy of Cure Alzheimer’s Fund is that we are unlikely to stop a disease that we don’t first truly understand,” said Chairman Jeff Morby. “This foundational work in understanding how synaptic signals affect—and are affected by—Abeta will no doubt bring us one step closer to our goal.”
In view of an emerging consensus on how Alzheimer’s disease develops and progresses, the Cure Alzheimer’s Fund Research Consortium aggressively is focusing on three opportunities for possible intervention—at the early stage of the disease, the middle stage and the late stage. This comprehensive strategy addresses the whole picture of how Alzheimer’s disease develops and progresses, and attacks all three points simultaneously.
What we know
For too long, Alzheimer’s research has been distracted by arguments over “plaques” vs. “tangles.” Some thought the key to treatment was clearing plaques, while others argued that eliminating tangles would cure the disease. Most researchers now agree it is necessary to attack both plaques and tangles, as well as other elements of the pathology, to stop the disease’s progression.
The Research Consortium now shares the understanding that Alzheimer’s is a vicious cycle of destruction that begins with the production of excessive beta-amyloid peptides (Abeta) that aggregate into clusters called “oligomers,” then proceeds to the creation of tangles from the protein tau that originate inside cells but that recently have been shown to spread to other cells. Both of these create inflammation in the brain, which stimulates more creation of Abeta, thus continuing a cycle that is deadly for brain cells. This destructive cycle can be envisioned as follows:
Intervention point - A
Ideally, this cycle would be stopped at what is thought to be its origin: the overproduction of the protein Abeta. This approach has been pursued broadly for a number of years, so far to little avail. Some drug candidates have proven too toxic; others were ineffective at safe doses. Recent research led by Robert Moir, Ph.D., of Massachusetts General Hospital (MGH) and funded by Cure Alzheimer’s Fund has shown the Abeta protein is an important and integral part of the innate immune system, and therefore maintaining an appropriate balance of the protein rather than eliminating it may be the right therapeutic approach.
Consortium researchers are pursuing a number of ways to control Abeta production and clearance. Perhaps the most promising research is taking place in the University of California, San Diego lab of Steven Wagner, Ph.D., and the MGH lab of Rudy Tanzi, Ph.D. Their approach has been to develop drugs to modulate an enzyme called gamma secretase, which is a critical contributor to Abeta production. Their effort has been so successful that the compounds they have developed have been adopted by the National Institutes of Health (NIH) as part of its fast-track, high-priority “Blueprint” program.
“We’re making excellent progress,” reports Wagner. “We have developed a number of compounds and are currently testing them with the hopes of narrowing the list down to one or two clinical candidates.” Tanzi echoes this optimism, saying, “We are hopeful that this project will lead to our gamma secretase modulators in clinical trials over the next year or so.”
Intervention point - B
In concert with efforts to contain Abeta in the earliest possible stage, consortium members also are pursuing strategies that would zero in on the formation and spread of tau tangles. Foremost among these is the effort led by consortium member David Michael Holtzman, M.D., based at Washington University in St. Louis, who recently demonstrated breathtakingly positive results in a proof-of-concept study aimed at stopping the aggregation and spread of tau in the middle stages of the disease.
Holtzman’s study, in collaboration with Washington University’s Marc Diamond, M.D., assembled a variety of potential tau antibodies and introduced them into the brains of genetically engineered mice. Based on a hypothesis that the toxic form of tau gets “spit out” of nerve cells and subsequently “infects” other nearby healthy neurons, the study demonstrated that the antibodies were able to conclusively stop this spreading process; this subsequently led to cognitive improvements in the mice. Their study was published in the journal Neuron in September 2013. The results were “fantastic,” commented the German Center on Degenerative Diseases’ Eckhard Mandelkow, Ph.D., to the Alzheimer’s Research Forum last September. “It explains why antibody therapy might work for tau pathology.”
Intervention point - C
Consortium members also are pursuing efforts to curtail Alzheimer’s-related brain inflammation. One of the most promising efforts involves an attempt to inhibit the activity of a gene called CD33. In 2008, Tanzi’s group first discovered this gene’s relationship to late-onset Alzheimer’s in a large family-based, genome-wide association study (GWAS). In 2013, the group described in the journal Neuron the gene’s regulation of immune-response microglial (helper) cells in the aging brain. Microglia normally clear away damaged and unwanted cells in the brain; if they are not functioning properly, damaging inflammation can occur. When Tanzi’s group deactivated CD33 in AD mouse models, more Abeta was cleared away by the microglial cells, leading to diminished amyloid plaque burden and less inflammation.
Project Reports on GlobalGiving are posted directly to globalgiving.org by Project Leaders as they are completed, generally every 3-4 months. To protect the integrity of these documents, GlobalGiving does not alter them; therefore you may find some language or formatting issues.
If you donate to this project or have donated to this project, you will get an e-mail when this project posts a report. You can also subscribe for reports via e-mail without donating or by subscribing to this project's RSS feed.