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.”
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.”
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."
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.”
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.
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:
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.”
Meet our funded researcher Giuseppina Tesco, M.D., Ph.D., assistant professor of neuroscience, Alzheimer’s Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine.
Born in Prato, Italy, in the heart of Tuscany, Giuseppina Tesco grew up with an older brother and two very open-minded parents. “My mother and father gave me a lot of freedom to make my own decisions about what interests I wanted to pursue,” says Tesco. “They were open to anything I wanted to do.”
Her interest in research began in high school when she would go to the library to study molecular biology, independently of what she was learning at school. “Molecular biology opened up a whole new universe for me and it made me want to know more.”
After high school, Tesco went to the University of Florence, where she earned her M.D. and then Ph.D. in neuroscience. “In Italy we don’t have college, so I went directly to medical school and did my residency in neurology there as well. My medical training was critical, but it also made me realize that I preferred being in a lab more than working with patients,” says Tesco. While in medical school in Florence, she sought out a lab opportunity in the field of psychiatry, but there wasn’t one. However, the neurology department, one floor below, had a research opening in a lab studying Alzheimer’s disease (AD). Tesco jumped at the chance.
While she was finishing her residency, Tesco met leading National Institutes of Health (NIH) Alzheimer’s scientist Daniel Alkon, M.D., at a conference in Florence. He offered her an opportunity to do her post-doctoral training on a Fogarty Fellowship at NIH in Bethesda, Md. “The work was similar to what I had been doing in Florence,” she says, “but I knew I would never have the same research opportunities in Italy as in the U.S.
“The move was really exciting for me,” she says. Tesco spoke only some English, but she learned quickly. At NIH she studied alterations of calcium levels in skin cells obtained from AD patients. Then she got a post-doctoral position at Massachusetts General Hospital working with Rudy Tanzi, Ph.D., to study the molecular aspects of Alzheimer’s disease in relation to its genetic components. “He has been a great mentor,” she says. “Rudy has always been dedicated to raising the next generation of scientists. I joined his lab as a post-doc and became an independent investigator in the unit that he is now directing.”
Cure Alzheimer’s Fund
In 2007, Tanzi asked Tesco to join Cure Alzheimer’s Fund’s research efforts to focus on a traumatic brain injury project. Since then, Cure Alzheimer’s Fund has supported two of her critical research projects: Traumatic Brain Injury and Stroke Relationship to Alzheimer’s Disease and Understanding the Role of the Gene ADAM10 in the Pathogenesis of Alzheimer’s Disease After Head Trauma.
Through her research, Tesco discovered a common pathway that is activated in the brain when patients suffer from either Alzheimer’s disease or acute brain injuries. “It wasn’t enough for me to know that there was a correlation—I needed to know why,” she says. Now, she wants to understand why traumatic brain injuries sometimes lead to other neurodegenerative diseases such as Parkinson’s disease or chronic traumatic encephalopathy. “I believe that your genes determine both if you will develop a disease and which disease you might develop, but I still need to know more. Cure Alzheimer’s Fund’s unique approach supports innovative research that can be high risk, but it can also lead to some very important findings.” Her next goal is to understand the mechanisms that link acute brain injury to chronic neurodegeneration to help get closer to the prevention and cure for Alzheimer’s disease.
In 2009, Tesco took a position at Tufts University in the neuroscience department, which allowed her to combine her knowledge of cell biology with the kind of research that is based on neuronal activity. At Tufts she has studied the disease in mouse models and has done a deep study on neurons, which she calls a great opportunity to advance the science.
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