Find all causes of Alzheimer's disease and a cure

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.”

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.

Early Days

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.” 

Education

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.