Alzheimer’s Disease Research
at MassGeneral Institute for Neurodegenerative Disease
The MassGeneral Institute for Neurodegenerative Disease houses ten separate laboratories that focus on AD, providing an extremely comprehensive effort on the multiple facets of this devastating disease. These coordinated efforts include hunting for genes that may predispose individuals to developing AD, molecular research that gives us clues about disease mechanisms, and screening potential drugs to prevent and treat AD. MIND has a wide-ranging enterprise underway to make sure that the latest scientific breakthroughs make a difference for patients.
MIND’s Genetics and Aging Research Unit, headed by Rudolph Tanzi, PhD, has firmly established itself as a world leader in discoveries relating to the genetics of Alzheimer’s disease. The Unit’s investigators found the first Alzheimer's disease gene, the beta-amyloid protein precursor (APP) which causes a rare “early-onset” form of the disease. Since then, they have identified and characterized several more genes that are implicated in AD. Most recently, Dr. Tanzi and Dr. Lars Bertram have found another mutation on the UBQLN1 gene on chromosome 9 that is associated with an increased incidence of Alzheimer’s in two large study samples comparing AD patients with their unaffected siblings.
This group of researchers led by Tanzi is currently leading the Alzheimer’s Genome Project. The massive project will include genotyping, analyses, follow-up, and confirmatory studies to identify the remaining Alzheimer’s genes that confer increased susceptibility to the disease.
In order to share the growing trove of genetic information and enhance the productivity of AD researchers, Dr. Lars Bertram collaborated with Dr. Rudy Tanzi to create the AlzGene database, hosted on AlzForum.org. The database is updated on a regular basis by Dr. Bertram and includes data from over 1600 AD gene studies. Over 300 AD gene candidates have been systematically subjected to meta-analysis and the results showing over 40 AD-associated genes are publicly available on the AlzGene.org website. This database allows interested scientists to find in one place detailed information about any gene that shows significant risk effects across a multitude of different study populations.
Basic Science - Important Discoveries about Alzheimer’s Disease
MIND houses a stellar group of scientists and physicians working to unlock the mysteries of Alzheimer’s disease. The breadth of research is astounding and provides numerous ideas for earlier diagnosis and better treatment.
In the Alzheimer’s Research Unit headed by Bradley Hyman, MD, PhD, more than 50 scientists from around the world use the latest technology to understand the development of Alzheimer’s disease over time and look for clues to prevent and reverse it.
Just as CT scans, MRI’s and PET scans have transformed medical care, new forms of microscopy and imaging have allowed MIND scientists to see inside the living brain to better understand Alzheimer’s disease pathology. Multi-photon microscopes, confocal microscopes, and laser capture microscopes are now used to see changes in both animal models such as mice, and in post mortem brains of patients, and to compare diseased brains with normal aging. As a result, we now have stunning visual records of the development of AD in mouse brains over time, as well as the clearance of AD plaques in mice by the application of therapeutic agents that act like vaccines against the protein pieces that form plaque in the brain.
This group also looks at the construction of neurons in the brain and how they are affected by AD plaques. Dr. Tara Spires, working in Dr. Hyman’s unit, has been able to study neurons’ dendritic spines -- small spider-like protrusions from the cell -- that are essential to the responsiveness and plasticity underlying learning and memory. She showed how AD plaques seem to cause the cells to lose spines and presumably, the connections between cells that are critical for making memories. Dr. Brian Bacskai and Dr. Matthew Frosch, working with Dr. Hyman, have used two-photon technology to examine amyloid deposits that build up within blood vessels in the AD mouse brain. These plaques, called cerebral amyloid angiopathy (CAA) are also found in humans, leading to risk for not only Alzheimer's disease but also stroke. The group’s findings showed that, unlike amyloid plaques that grow between brain cells in AD, these vascular deposits grow at a consistent rate, making CAA a useful system in which to assess the effectiveness of treatments intended to prevent growth or promote clearance of amyloid deposits in the brain.
In the Genetics and Aging unit at MIND, scientists use gene discovery to determine how inherited defects in AD genes lead to changes at molecular and biochemical levels and serve to cause or increase susceptibility to AD. Their goal is to determine exact points in genetically-disrupted biological pathways where one could pharmacologically intervene to treat or prevent AD.
One area that has recently emerged is the role stroke, head trauma, seizures and the use of anesthesia in the development of Alzheimer’s disease. It is hypothesized that these insults to the brain can trigger a series of biochemical events that increase beta-amyloid production in the brain, which in turn increases plaque formation. Researchers Giuseppina Tesco, MD, Zhongcong Xie, MD and Dora Kovacs, PhD found in separate studies that traumatic events lead to an increase in the enzyme beta secretase (BACE) which cleaves the APP protein into amyloid. Novel therapies could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients.
Dr. Wilma Wasco's laboratory is focusing on genes that are responsible for the degeneration of brain cells that is typical of both AD and normal aging. Dr. Wasco's lab has been directly involved in the identification and characterization of a number of such genes - two amyloid precursor-like proteins (APLP1 and APLP2), both of the presenilin proteins (PS1 and PS2) and calsenilin, a protein that interacts with presenilin and also binds to calcium. Her laboratory strives to understand the biological role that each protein plays in both the normal and the aging brain and to determine how disease-associated gene mutations change normal functioning. With a better understanding of how these proteins damage nerve cells in the brain, therapies that block the process can be developed.
Dr. Dora Kovac’s laboratory studies the pathways that regulate the generation of the beta-amyloid protein in brain cells, and the factors involved in the subsequent brain cell death. Several lines of evidence suggest that cholesterol is a major risk factor in the pathology of AD and so her group studies the role of cholesterol in beta- amyloid protein production. The ultimate goal of this project is to design and test strategies to interrupt cholesterol’s effect on this toxic process.
MIND researcher Suzanne Guenette, PhD continues her important study of proteins that interact with APP- the amyloid precursor protein- a central target in Alzheimer's disease. Dr. Guenette's work is focused on examining the proteins that interact with APP to see if we can better understand the function of APP and find possible interventions to reduce its toxicity. Guenette has focused on the FE65 proteins which bind to APP-- showing that without Fe65 proteins, mice show severe abnormalities in the brain’s cortex, similar to mice lacking all APP proteins, thus suggesting that these proteins must work together for neural development. Recent studies have also shown that the FE65-binding region of APP has been implicated in the development of AD in mouse models. All this work suggests that targeting the FE65’s, instead of APP directly, may be an alternative way to affect disease progression in Alzheimer’s.
Biomarkers and Diagnosis
In Alzheimer’s disease, physicians usually make a probable diagnosis by ruling out other causes of dementia, since the hallmarks of the disease – plaques and tangles in the brain – can only be seen at autopsy. As we approach a time when treatment and prevention are possible in this disease, early diagnosis, as well as the ability to track disease progression biologically over time, is extremely important. This will allow us to measure how well a particular therapeutic works to slow or reverse disease progression, and to intervene with treatment even before there are symptoms such as memory loss.
Dr. Hyman’s laboratory has been at the forefront of imaging the brains of live mice with 2-photon confocal microscopy. This imaging provides never-before-seen observations directly on the plaques that develop in the transgenic mouse models of AD, and has led to several dramatic breakthroughs including showing that plaques (and presumably the disease) can be reversed by therapeutic application of antibodies -- a “vaccine” approach to treatment.
Dr. Brian Bacskai and Dr. Matthew Frosch have used this technology to examine amyloid deposits that build up in blood vessels in the AD mouse brain. Their goal was to visualize in real time the initiation and progression of CAA in live mice. The group’s findings showed that, unlike amyloid plaques that grow between brain cells in AD, these vascular deposits grow at a consistent rate. This consistent feature makes the measurement of CAA a useful system in which to assess the effectiveness of candidate treatments intended to prevent growth or promote clearance of amyloid deposits in the brain.
The laboratory is now actively involved in developing the next generation of dyes that specifically bind to plaques in humans in order to track disease progression before symptoms begin, using PET scans or other imaging devices. This exciting work will ultimately allow physicians to order tests that can identify patients at high risk of developing memory problems and Alzheimer’s disease, and to proactively treat these patients and prevent or slow disease progression.
Basic Science Leads to Ideas for Drug Discovery
At MIND, researchers are focused not only on understanding how devastating changes in the brain occur at the cellular and molecular level, but also how to interrupt this disease process with potential drugs. Many of the researchers have developed “assays” or petri-dish cell models of the disease for use in screening potential compounds for drug development. Screening can then be done at MIND in our high-throughput drug screening facility headed up by Dr. Alex Kazantsev, or with other partners in academia or industry. In addition to screening new compounds, researchers can also look for existing drugs or vaccines with the potential to slow disease onset or progression.
For example, Dr. Kovac’s research to understand the role of cholesterol in the processing of beta-amyloid and the development of toxic plaques in the brain has immediate implications for drug discovery. A study led by Dr. Kovacs is testing drug compounds that are known to alter cholesterol production to see if they could prevent or decrease the production of beta-amyloid. These drugs, a class of statins called ACAT inhibitors, were originally developed for heart disease, but may also help prevent Alzheimer’s disease.
Dr. Hyman’s work examining amyloid in the brain of living mice has led to the development of antibodies that will stimulate the body’s own immune system to clear toxic amyloid from the brain. His group has demonstrated the efficacy of this approach in mouse models; pharmaceutical companies have been able to initiate human studies based on this strategy.
Clinical studies on promising therapies are coordinated through the MGH Memory Disorders Unit and the Massachusetts Alzheimer’s Disease Research center, in partnership with researchers at MIND. The Massachusetts Alzheimer’s Disease Research Center, which incorporates researchers at MIND, MGH, and other Harvard Medical School institutions, provides top-notched, compassionate diagnosis and treatment to individuals with AD and other forms of cognitive impairment, as well as state-of-the-art neuroscience research directed towards uncovering the causes and treatment of AD and memory problems.
To accomplish this goal, we research ways to improve early diagnosis and tracking of the disease and also conduct clinical trials to test new drugs. Thanks to extremely generous patients who donate brains at the time of death, we also perform anatomical and biochemical analyses on postmortem brain tissue on both normal brains and those who have been affected by Alzheimer’s disease. A database that links all the clinical, pathological and genetic information collected from patients enrolled in studies at the Massachusetts General Hospital allows powerful analysis of the multiple factors involved in the development of Alzheimer’s and the other neurodegenerative disorders.
Find out more about clinical studies on the Memory Disorders Unit Clinical Trials page.