Identify/understand all Alzheimer's-related genes

 
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Mar 5, 2014

Drug Development Strategy: Three Points of Attack

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

Early stage

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

Middle stage

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

Late stage

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.

Dec 16, 2013

Cholesterol and Alzheimer's: A Big Step Forward

Dora Kovacs
Dora Kovacs

What is the relationship between cholesterol and Alzheimer’s disease, and when might that connection lead to disease-limiting medications?

New research funded by Cure Alzheimer’s Fund has helped advance these questions in a significant way. 

For more than a decade now, researchers have been aware of important links between cholesterol and Alzheimer’s disease. Studies have shown that cholesterol levels are a significant risk factor in developing the disease, and that cholesterol-limiting statins might lower this risk. Further investigation has revealed that cholesterol somehow regulates the production of the toxic protein fragment Abeta, a central player in Alzheimer’s. 

But researchers have been struggling to define the precise cholesterol-Alzheimer’s relationship. How does cholesterol assist or instigate the production of Abeta? 

One step closer to a potential drug

A new study by Dora Kovacs, Ph.D., Raja Bhattacharyya, Ph.D., and Cory Barren, M.Sc., at Massachusetts General Hospital provides a specific answer, and brings us one step closer to a potential drug that might interrupt the disease process. 

This is not the first important contribution to this issue by Dr. Kovacs and colleagues. In 2001, they identified a specific enzyme in the cholesterol pathway, abbreviated as ACAT, involved in the production of Abeta. By inhibiting ACAT, they demonstrated that Abeta production also can be reduced.

 

In a newly published paper in the Journal of Neuroscience, they identify a specific mechanism of action that accounts for this relationship between ACAT and Abeta production. The process, known as “palmitoylation,” involves the attachment of fatty acids to pieces of a membrane protein.

The team also used two known ACAT inhibitors previously designed to reduce cholesterol to actually reduce Abeta production. They conclude that using these inhibitors “would appear to be a valid strategy for prevention and/or treatment of Alzheimer’s disease.”

This careful work points to more potential therapies for Alzheimer’s disease through the use of existing or future cholesterol-lowering drugs. “Our hope,” Dr. Kovacs said, “is that one or more ACAT inhibitors currently in clinical trials for cardiovascular disease can be used for Alzheimer’s disease in the near future.”

Breakthrough research

In recent decades, targeting cholesterol has helped to radically advance the prevention and treatment of heart disease. This accumulation of research suggests we might be on the cusp of achieving the same thing with Alzheimer’s.

“This is exactly the sort of groundbreaking research we set out to support,” said Cure Alzheimer’s Fund Chairman Jeff Morby. “In fact, Dr. Kovacs’ earlier cholesterol research was the very first project supported by Cure Alzheimer’s Fund. Alzheimer’s research is arduous, but having persevered and followed the facts, we’re now one important step closer to a useful treatment.”

Oct 1, 2013

Two Late-Onset Gene Mutations Identified

Rudy Tanzi
Rudy Tanzi

In a paper just published in the prestigious journal Neuron, Harvard Medical School/Mass General Hospital Geneticist Dr. Rudy Tanzi, together with lead author, Dr. Jaehong Suh and their team, identified two rare mutations in the human gene called "ADAM10" that lead to the most common, late-onset variant of Alzheimer's. Tanzi's research suggests that the ADAM10 gene makes an enzyme called alpha-secretase, which cleaves the Amyloid Precursor Protein (APP) to prevent the formation of beta-amyloid, the toxic protein that triggers brain pathology in Alzheimer's disease.

This new landmark genetic discovery by Rudy Tanzi, who is also Research Consortium Chair at Cure Alzheimer's Fund, further buttress the widely-held "Amyloid Hypothesis" and suggest specific new therapeutic approaches to stopping Alzheimer's disease.

In their study, Tanzi and Suh first identified two new human gene mutations in ADAM10 and then inserted them into Alzheimer's mouse models to track their effects in the brain. Subsequently, the team was able to demonstrate how the mutant genes diminish alpha-secretase activity and led to increased levels of beta-amyloid, the main component of senile plaques in Alzheimer’s disease. 

These findings are the first to document novel Alzheimer's gene mutations in animal models since the mutations in the original four Alzheimer's genes – APP, PSEN1, PSEN2, and APOE – were discovered in the 1990’s.

Furthermore, the effects in mouse brains strongly suggest that diminished alpha-secretase activity owing to the ADAM10 gene mutations causes Alzheimer's and therefore support ADAM10 as a promising therapeutic target for the treatment and prevention of the disease. "If we can find or develop a drug to safely increase alpha-secretase activity," said Tanzi, "that would decrease the accumulation of beta-amyloid plaques and slow down or even stop the onset of the disease."

Cure Alzheimer’s Fund president and CEO Tim Armour says: "These discoveries are validation of the aggressive gene-centric approach long supported by Cure Alzheimer's Fund. With this new data, we have two more important pieces filling out the large puzzle of how Alzheimer's disease develops in the human brain. It's that much closer to a complete picture, and brings us that much closer to a cure."

Links:

Jul 17, 2013

Public-Private Effort Yields Key Progress

An innovative new public/private collaboration between Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH) already has started to bear fruit. 

In May, NIMH announced it would invest $4 million into Cure Alzheimer’s Fund’s ambitious Whole Genome Sequencing Project (WGS), which will speedily map out the entire genome’s connections to Alzheimer’s disease. This sequencing project, which covers the 97 percent of the genome that until very recently was regarded widely as “junk DNA,” is the largest single-disease, family-based Alzheimer’s investigation of its kind. Cure Alzheimer’s Fund already has allocated $5.4 million to the venture, and is committed to raising the remaining $1.5 million to complete the project.

The Whole Genome Sequencing Project process will go beyond previous techniques to allow researchers to understand the genetic switches controlling Alzheimer’s genes and how they are triggered by other genes and by environmental inputs. It also will yield an enormous amount of data, which will be analyzed using sophisticated bio-informatics (mathematical algorithms). Over the next several months, the study will begin analyzing the complete genomic sequences of more than 1,500 subjects in Alzheimer’s-affected families. Researchers then will compare the human genome sequences from family members with and without the disease to identify precisely all of the variations in our genomic DNA that influence the development of Alzheimer’s.

This CAF-NIMH partnership already is paying off.

The journal Neuron recently published results of a breakthrough discovery made by Rudy Tanzi, Ph.D., chairman of the Cure Alzheimer’s Fund Research Consortium, and colleagues at Massachusetts General Hospital, and co-funded by Cure Alzheimer’s Fund and NIMH. Tanzi found that excessive levels of the protein CD33 can impede the clearance of the plaque-forming protein Abeta, the key component of senile plaques in the brains of Alzheimer’s disease patients. “Too much CD33 appears to promote late-onset Alzheimer’s by preventing support cells from clearing out Abeta-containing plaques,” explains Tanzi.

Director of NIMH Thomas R. Insel affirmed the finding’s importance. “These results reveal, for the first time, a potentially powerful mechanism for protecting neurons from damaging toxicity and inflammation in brain disorders,” says Insel.

Funding for Alzheimer’s research consistently has lagged behind that for other major diseases, badly impeding research. “Based on what we have learned so far, we have many more good ideas than funding will allow us to explore,” says Tanzi. This trailblazing public/private endeavor allows the Alzheimer’s research community to begin the process of catching up.

“We can leverage private funds into a much stronger overall effort,” says Jeff Morby, chairman and co-founder of Cure Alzheimer’s Fund. “The WGS data will speed development of therapies, both to prevent the disease and arrest its progress. We are most grateful to the NIMH for partnering with us in this pioneering effort.”

“We are taking advantage of cutting-edge technology to discover exactly how our genes determine susceptibility to Alzheimer’s disease,” says Tanzi. “We will then use this knowledge to guide novel drug discovery efforts.”

May 29, 2013

Launching the Stem Cell Consortium

Stem cells long have been the mythical Excalibur of Alzheimer’s disease research—imbued with almost magical qualities that could allow us to conquer this nearly impossible disease. For decades, though, hope has outshone reality.  

The Opportunity  

This ambitious new project was funded by a generous group of individuals, foundations and trusts—without which exploring this new frontier would not be possible. 

The Power of Stem Cells

Stem cells are different from all other human tissue in three important, unique ways. First, they are unspecialized. Second, they can renew themselves by cell division. Third, they can be directed under certain conditions to become a wide variety of permanently specialized cells. In 1981, scientists discovered how to isolate embryonic stem cells from mouse embryos; in 1998, they devised how to grow human embryonic stem cells in a laboratory.  

The more recent breakthrough is the ability to genetically induce a specialized adult cell, such as a common skin cell, into reverting back to an unspecialized stem cell. Once generated, these pluripotent stem cells (iPS’s) are able subsequently to be directed to become a specialized cell—such as a neuron.  

Thus, an ordinary skin cell can now, in a lab, be converted into a neuron. From here, the hope is to create a new universe of Alzheimer’s nerve cells living outside the human brain in order to study and test new drugs much faster than researchers currently are able. To get there, the seven-member stem cell consortium, assembled by Sam Gandy, M.D., Ph.D., at Mount Sinai Medical Center, will have to first complete a number of precise tasks:

  • ·         Generate iPS cells and neurons from the skin cells of Alzheimer’s patients. This already has been accomplished by Scott Noggle, Ph.D., of the New York Stem Cell Foundation and Kevin Eggan, Ph.D., of the Harvard Stem Cell Institute. Mark Tessier-Lavigne, Ph.D., president of The Rockefeller University, also has done important Cure Alzheimer’s Fund-funded work to determine the best method for obtaining these cells.
  • ·         Perform molecular and biochemical analysis of new laboratory neurons. The newly converted Alzheimer’s neurons can be examined both in a laboratory dish and by transplanting them into the brains of host mice. Dr. Gandy already has discovered amyloid beta metabolism abnormalities in the Alzheimer’s neurons. Future studies will examine how the neurons respond to various stresses.
  • ·         Profile the Alzheimer’s neurons. Drs. Noggle, Eggan and Gandy will establish a baseline molecular characterization of nerve cells from Alzheimer’s patients to determine the similarities and differences between those neurons and non-Alzheimer’s neurons.
  • ·         Generate human neurons
    with known Alzheimer’s genes. Dr. Doo Yeon Kim, Ph.D., will establish various Alzheimer’s cell models designed to overexpress various known genetic mutations in order to enhance Alzheimer’s pathology.
  • ·         Plant the new human neurons in mouse brains. Drs. Kim and Tanzi will establish a method to graft newly created neurons into mouse brains and analyze various disease markers in the months after cell injections. Tamir Ben-Hur, M.D., Ph.D., of Hadassah University Medical Center in Jerusalem will help choose which genetically manipulated mice are most likely to accept a stem cell transplant, and will guide the manipulation of these substances using small molecules and drugs in order to determine how best to keep stem cells alive.
  • ·         Identify functional properties of human Alzheimer’s cells. Ben-Hur will conduct various tests on lab-created Alzheimer’s neurons inside and outside of mouse brains. He will gather new information on how Alzheimer’s neurons survive and connect in the brain environment.
  • ·         Create a new choline acetyltransferase (ChAT) human pluripotent reporter cell line. Dr. Eggan will attempt to create a new cell line for studies into the in vitro generation of human cholinergic neurons.

Together the CAFSCC team will develop, study and maintain Alzheimer’s neurons that will be used to screen for new drugs. In keeping with Cure Alzheimer’s Fund’s principle of openness, this stem cell “bank” also will be made available to other researchers throughout the world. “We have great expectations for this project,” said Tanzi. “It could greatly accelerate the process of drug discovery.”

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Organization

Cure Alzheimer's Fund

Wellesley Hills, Ma, United States
http://www.curealzfund.org

Project Leader

Laurel Lyle

Wellesley Hills, MA United States

Where is this project located?

Map of Identify/understand all Alzheimer's-related genes