ALZHEIMER’S DISEASE RESEARCH at the SALK INSTITUTE
INTRODUCTION A WORM’S If, in the end, we are the sum of our memories and experiences, then Alzheimer’s disease LIFE acts as a great eraser, wiping out who and what we are. First described by German psychiatrist Dr. Alois Alzheimer in 1906, the brains of Alzheimer’s patients are riddled with amyloid plaques and neurofibrillary tangles. Finally, after decades of research, scientists at the Salk Institute and BETA AMYLOID AGGREGATES FORM AS A SIDE elsewhere have gained insight into the molecular basis of this devastating disease. EFFECT OF THE AGING PROCESS Salk professor Dr. David Schubert was among the first to study the biological functions of beta ike most neurodegenerative diseases, Alzheimer’s disease amyloid, the major constituent of the plaques. Since then, Salk researchers have made progress explaining how the toxic protein clumps form and they have developed gene therapy models in L usually appears late in life. This raises the question whether Alzheimer’s is a disastrous side effect of the aging process itself mice that appear to reverse the formation of these plaques. They have also discovered that our or whether it just takes a long time for the characteristic brain can sprout new neurons throughout life and coax stem cells to mature into new brain cells. abnormal plaques to form in the brain. To find out, Dr. Andrew Dillin and his team employed the help of tiny Methuselah worms Today, Salk faculty members from various fields of science steadily chip away at the mystery that—despite their advanced age—still have a youthful spring in their crawl. These of Alzheimer’s disease and continue to provide hope through basic research. indefatigable creatures proved that slowing down the aging process also reduced the formation of toxic beta amyloid aggregates. Dr. Dillin discovered that beta amyloid Here are some of their stories. aggregates started to form in aged worms when their cellular detoxification machinery could no longer keep up. This insight may point scientists in new directions to develop drugs for the treatment of Alzheimer’s and other neurodegenerative diseases.
OLD BRAINS, LET’S NEW TRICKS TALK MENTAL AND PHYSICAL EXERCISE ALIKE REJUVENATE THE BRAIN WHEN SCIENTISTS MEET, NEURONS FIRE AND SPARKS FLY ust about everybody assumed that we are born with all the brain cells, or neurons, we will J ever have. Then Dr. Fred H. Gage and his team came along and toppled this long-held J onas Salk believed that getting scientists to talk with each other would spark great ideas, and so does John Adler, belief with a groundbreaking experiment that showed human brains sprout new neurons Dr. Fred H. Gage (left) and Mr. John Adler throughout life, particularly in the hippocampus — the brain’s learning and memory center. a longtime member of the Salk Institute’s Board of Trustees. The exact function of these newcomers is still unclear, although a few studies have linked To foster communication between Alzheimer’s disease researchers, he initiated, funded, and them to the beneficial action of certain anti-depressants as well as to learning and memory. ultimately endowed an internationally renowned Alzheimer’s symposium. For the last 15 years, nearly 50 scientists from around the world who are interested in topics related to the brain and Alzheimer’s Dr. Gage also discovered that physical activity such as running boosts the number of new disease have been congregating annually at the Salk Institute to bounce ideas off one another. neurons and improves learning and memory in mice, even elderly ones. Today, neurobiologists no longer argue about whether the brain can grow new cells. Instead, they are trying to During one of these gatherings, two regular attendees harness the brain’s capacity to sprout were discussing Dr. Gage’s discovery and decided new cells from its reserve of stem to take it one step further. Hoping that mice prone to cells in order to treat disorders Alzheimer’s disease would benefit from boosting the ranging from Alzheimer’s and numbers of new neurons, they raised mice bred with Parkinson’s to depression. an Alzheimer’s gene in an enriched environment— large cages filled with running wheels, colored tunnels, and playmates. Mice living in the deluxe setting took almost twice as long as their counterparts living in bare standard cages to develop symptoms of Alzheimer’s disease. “Enrichment” via physical and mental exercise is now a key tool in the treatment program for Alzheimer’s disease at leading health organizations, proving the power of communication.
FATAL SWEET ATTRACTION DEFENSE A SHAPE CHANGE PRECIPITATES UPPING SUGAR CONSUMPTION PROTECTS THE BRAIN AGAINST TOXIC PROTEIN AGGREGATES ALZHEIMER’S PLAQUES lumps of abnormal protein that the he telltale plaques that pepper the brains C brain cannot dispose of are at the T of Alzheimer’s patients consist mainly of heart of many, if not all, neurodegenerative the beta amyloid protein. Although the diseases. Masses of the beta amyloid production of beta amyloid occurs in everyone, protein form the “senile” plaques seen in healthy brains are able to clear away excess Alzheimer’s disease; prion protein deposits amounts. Accumulation of the toxic protein, cause the brain’s severe destruction that however, stimulates the production of free characterizes “mad cow disease”; and radicals, oxygen-containing molecules that alpha synuclein aggregates are associated attack many of the cell’s major components. with Parkinson’s disease. Dr. Roland Riek At high levels, free radicals can kill brain cells and his colleagues discovered that this altogether. But not all brain cells in motley group of proteins shares a common Alzheimer’s patients die. capability: They all can flip from a rather flexible and fully functional shape to a rigid, pleated structure called a beta sheet. Dr. David Schubert and his team discovered that many cells survive the same toxic Irresistibly attracted to each other, these beta sheets stack up like empty egg cartons, conditions that kill their neighbors. He found that low amounts of beta amyloid increase precipitating a chain reaction that causes toxic protein aggregates to form. Further the brain’s consumption of glucose, a form of sugar. Increased glucose metabolism aids the Salk Institute studies to understand this transformation process will have a profound production of scavenger molecules that “soak up” free radicals and render them harmless. impact on explaining the underlying mechanisms of these disorders, as well as on efforts Thus protected, the cells can withstand the onslaught of high amounts of beta amyloid. to develop novel therapies to treat them. Understanding how the brain protects itself against oxidative stress provides scientists with a way to possibly manipulate this biological process as a means of therapy.
TAXI UNTANGLING VIRUS ALZHEIMER’S GENE THERAPY REVERSES COURSE OF ALZHEIMER’S DISEASE IN MICE A VERSATILE ENZYME RESTORES THE SHAPE OF A KEY PROTEIN any devastating diseases such as cystic r. Tony Hunter and his team identified human enzyme Pin1 when they fished for M fibrosis, muscular dystrophy, and sickle D proteins that play a role in the regulation of cell division in the obscure mold Aspergillus cell anemia can be traced to a defect in a nidulans. They quickly established that Pin1’s job is to latch onto other proteins when single gene. Curing the disease by replacing phosphates are added to flip their shape. But little did the team know that they had hooked the afflicted individual’s defective gene with a a versatile, all-round talent that plays a central role in driving cell proliferation and © 2006 Alzheimer's Association. All rights reserved. correct copy is the elegantly simple promise of preventing age-related neurodegeneration. gene therapy. Dr. Inder Verma and his colleagues pioneered the use of stripped-down Blocking Pin1 kills cells as they attempt to divide, and several drug companies are already versions of viruses, particularly HIV, to taxi the searching for substances that turn off Pin1 and wipe out fast-dividing cancer cells in the much-needed genes to cells throughout the process. But in the manner of a true Jack-of-all-Trades, Pin1 can also restore the normal body and permanently insert them into the shape of tau, the protein that forms the knotty tangles that skew the communication cells’ DNA code. between brain nerve cells in Alzheimer’s disease patients. In a Dr. Verma successfully extended the use of gene therapy to mice that had been genetically new twist, Pin1 may also slow the engineered to develop Alzheimer’s. His taxi virus successfully ferried neprilysin, an enzyme production of plaque-forming beta that has the ability to degrade beta amyloid, into the mice’s brain cells. In a radically amyloid and prevent its aggregation. different approach, he was able to reverse the rodents’ memory loss by silencing—instead of These findings are an important step adding—an enzyme that is crucial for the development of Alzheimer’s disease. Currently, toward understanding the molecular Dr. Verma and his team are hard at work to perfect their techniques in mice, hoping to soon mechanisms underlying the be able to test their approach in monkeys. development of Alzheimer’s disease and may help in the quest for effective treatments. Brain Changes of Brain Slice by Jannis Productions: Rebekah Fredenburg, computer animation; Stacy Jannis, illustration/art direction.
COMMUNICATION CAREER BREAKDOWN DECISIONS A BETA AMYLOID FRAGMENT INHIBITS COMMUNICATION BETWEEN BRAIN CELLS FOR NEURONAL STEM CELLS, LOCAL ENVIRONMENT emory deficits and the loss of connections between brain cells precede the visible FUNCTIONS AS M damage that ravages the brains of Alzheimer’s patients in latter stages of the disease. GUIDANCE COUNSELOR This finding provoked scientists to ask new questions about the disease: What if it is caused everal years ago, Dr. Fred H. Gage’s by defective synapses—the specialized communication interfaces between neurons—and dying brain cells are just the result of gummed-up connections? This new concept led S discovery of brand new nerve Dr. Stephen Heinemann to study the communication between nerve cells in mice that cells, or neurons, in the brains of overproduce a mutant form of the human amyloid precursor protein (APP) from which a fully grown humans flew in the face number of smaller fragments, one of them known as beta amyloid, are cleaved off. of conventional wisdom. Perhaps even more exciting was the finding He and his colleagues discovered that the that the source of these new cells transmission of signals between brain cells in was brain stem cells—unspecialized these mice is severely hampered long before the progenitors with the ability to morph first signs of toxicity and cell death appear. The into any type of brain cells. To tap interrupted cell-to-cell communication could their full potential, adult stem cells explain the loss of memory that is apparent in in the brain and elsewhere require additional nudging by their neighboring brain cells to early stages of the disease. On closer inspection, turn into fully specialized cells. Dr. Gage and his team identified a crucial cellular signal, © 2006 Alzheimer's Association. All rights reserved. Dr. Heinemann discovered that a short APP the wnt3 molecule, that controls whether a stem cell becomes a neuron. Identifying the fragment may be the culprit. Blocking the molecular instructions that push neuronal stem cells down a certain path of specialization cleavage of APP should stall the progression of is a first step toward generating the exact cell types needed to replace brain cells damaged the disease or even make it possible to recover by traumatic injury or degenerative disease such as Parkinson’s, Alzheimer’s, stroke, and lost memory function. epilepsy, as well as depression. The Neuron Forest by Jannis Productions: Rebekah Fredenburg, computer animation; Stacy Jannis, illustration/art direction.
SALK FACULTY CURRENT SALK FACULTY MEMBERS WHOSE RESEARCH IS RELATED TO ALZHEIMER’S AND OTHER NEURODEGENERATIVE DISEASES: DR. ANDREW DILLIN, Assistant Professor and Pioneer Developmental Chair, Molecular and Cell Biology Laboratory DR. TONY HUNTER, American Cancer Society Professor, Molecular and Cell Biology Dr. Dillin focuses on aging and neurodegeneration, using the worm C. elegans Laboratory, Dulbecco Laboratory as a research model. Further elucidating the process of aging in this simple Dr. Hunter studies how cells regulate their growth and division, and how organism will lead to a better understanding of human diseases associated with mutations in genes that regulate growth lead to cancer. aging, such as cancer, diabetes, and neurodegenerative diseases. DR. FRED H. GAGE, Professor and Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases, Laboratory of Genetics DR. ROLAND RIEK, Associate Professor and McLoraine Chair in Neurobiology, Structural Biology Laboratory Dr. Gage concentrates on the adult central nervous system and the brain’s Dr. Riek studies protein structures, particularly the steps that occur when unexpected adaptability to environmental stimulation that remains throughout proteins misfold. Such misfolding problems can result in malfunctions in the the life of all mammals. His work may lead to methods of replacing or enhancing cellular machinery, including Alzheimer’s disease and transmissible spongiform brain and spinal cord tissues lost or damaged as a result of neurodegenerative encephalopathy, which includes the so-called “mad cow disease.” diseases or trauma. DR. STEPHEN HEINEMANN, Professor, Molecular Neurobiology Laboratory DR. DAVID SCHUBERT, Professor, Cellular Neurobiology Laboratory Dr. Heinemann studies the molecular details of communication among brain cells. Since neurological ailments such as Alzheimer’s and Parkinson’s, drug Dr. Schubert studies hormones and other substances that affect the activities and addiction, and mental disorders such as depression and schizophrenia are survival of brain cells. Much of his research is providing new insights into fundamentally disorders of brain cell communication, his research will provide Alzheimer’s disease and other degenerative brain disorders. new insights into the treatment of these disorders. DR. INDER M. VERMA, Professor and American Cancer Society Professor, Laboratory of Genetics Dr. Verma is developing carriers for gene therapy. Replacing faulty genes with normally functioning genes provides a way to fix a problem at its source and treat hereditary diseases and cancer.
SALK TODAY erhaps no other condition robs its victims of their sense of identity the way Alzheimer’s P disease does. As the average age of the U.S. population climbs, the number of people ravaged by Alzheimer’s disease continues to rise. Half of all people who reach age 85 are likely to be affected by this devastating disease. Basic scientific research is the key to both finding drugs to prevent Alzheimer’s and possibly reversing its effects when caught early. Understanding the biological processes that trigger the disease is critical to developing effective therapies that will stop its progression or, better yet, prevent it altogether. If you would like to learn more about Alzheimer’s research conducted at the Salk Institute, please call the Institute Relations office at 858.453.4100, ext. 2062 or e-mail email@example.com. Special thanks to the members of the White Dragon School in Mira Mesa and to Laura Johansen of San Diego's Alzheimer's Association for their friendly help with the production of this publication.
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