Alzheimer's Disease

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Contrary to those static diagrams of a cell you may remember from high school biology, a eukaryotic cell (cell with a nucleus) is actually a dynamic and intricately ordered living creature, complete with its own set of tiny "organs" and empowered by thousands of chemical mechanisms that enable the cell to digest, reproduce, move and communicate with other cells.

The remarkably complex anatomy of all eukaryotic cells and many of their basic molecular mechanisms are strikingly uniform in the 60 trillion cells comprising the human body. Cell biologists relate these features to cellular functions by determining the molecular mechanisms responsible for fundamental processes ranging from cell division and protein transport to signal transduction and the migratory behavior of cells underlying tissue formation during embryonic development and wound healing.

It follows that an understanding of normal cells paves the way for a greater comprehension of a variety of human diseases, says Robert D. Goldman, Stephen Walter Ranson Professor and chair of cell and molecular biology at The Feinberg School of Medicine.

"All disease results from failed mechanisms within cells. Analyzing the workings of healthy cells will lead to development of targeted therapies, improved methods for facilitating wound healing, development of artificial tissues and a better understanding of the potential uses of human stem cells," he said.

Goldman is a highly regarded authority on the structure and function of the cytoskeleton. His other passion in science lies in the area of the public’s understanding of science and technology. With Boyce Rensberger, award-winning former science editor of the Washington Post, he directs the Science Writers Fellowship Program at the Marine Biological Laboratory in Woods Hole, Mass., which offers journalists the opportunity to gain hands-on experience with the laboratory techniques used by biomedical researchers.

In his 20 years as chair, Goldman has overseen the development of a department that now ranks in the top 10 of its peer departments in 126 U.S. medical schools (American Association of Medical Colleges data). This year, CMB faculty were awarded approximately $10 million in grant funding from the National Science Foundation and the National Institutes of Health, including several MERIT awards and Program Project Grants (PPGs).

The department is home to a number of scientists whose body of research has been honored both nationally and internationally. Laszlo Lorand and Edwin Taylor are members of the National Academy of Sciences and the American Academy of Arts and Sciences.

Lorand, who joined Northwest-ern in 1955, is one of the world’s leading experts on blood clotting mechanisms. Taylor, widely acknowledged as one of the "fathers of cytoskeletal research," received the E. B. Wilson Medal, the highest honor awarded by the American Society for Cell Biology. He also is a member of the Royal Society of London.

Three researchers, including Goldman, currently have prestigious MERIT (Method to Extend Research in Time) awards from the NIH for outstanding records of scientific achievements. The other recipients are Lester I. (Skip) Binder and Linda Van Eldik for their work on Alzheimer’s disease. Previous MERIT award recipients in the department include Lorand, Arthur Veis and Gary Borisy, Leslie B. Arey Professor of Cell, Molecular and Anatomical Sciences. Borisy is currently the president of the American Society for Cell Biology.

Department researchers employ a broad range of technological methods, including biochemical, biophysical and immunological approaches, as well as digital and confocal microscopy, video-enhanced light microscopy and molecular biological and genetic manipulation of function at both the cellular and organismal level.

For this article, the work of these investigators is described by areas of research: cytoskeleton; cell surface/extracellular matrix; molecular mechanisms and the nucleus; and the cellular basis of disease, emphasizing Alzheimer’s disease. (The department also includes a group of physical anthropologists who were featured in an earlier OBSERVER article.)

The cytoskeletal group studies one or more of the three major "scaffolding" components of mammalian cells, including actin, microtubules and intermediate filaments.

The pioneering research of Gunther Albrecht-Buehler, Robert Laughlin Rea Professor of Cell and Molecular Biology, attempts to integrate all of the cells’ cytoskeletal and molecular activities that are responsible for regulating cellular behavior patterns. His work on the role of the centrosome, a structure located near the nucleus and the microtubule organizing center of the cell, suggests that the centrosome is the "brain," or unifying system, that controls cell motility.

The Borisy lab is internationally recognized for groundbreaking studies of the function and organization of microtubules, filamentous structures that course through the cell and act as "tracks" on which protein complexes called "molecular motors" use energy to move other "molecular cargo" from one part of the cell to another. Borisy’s group also studies the organization and dynamics of actin which, in addition to a multitude of its other duties, is essential to processes involved in cell migration and, hence, embryonic development.

James Bartles investigates the role of espin, a cytoskeletal protein he discovered, which is present throughout the nervous system and is a key structural component of the stereocilia of hair cells, the apparatus in the inner ear that detects sound and motion and helps control balance in the body. His research showed that a defect in the espin gene causes abnormal behavior in mice (the animals appear to dance) and also renders them deaf. For this work, Bartles recently received a five-year grant from the National Institute on Deafness and Other Communication Disorders of the NIH.

Rex Chisholm, who also is the director of the Center for Genetic Medicine, studies the myosins, a class of molecular motors that interact with actin to power cell motility and facilitate a wide range of processes ranging from intracellular transport to cardiac and skeletal muscle contraction. Myosin motors have been linked to numerous human diseases, including hypertrophic cardiomyopathy, the leading cause of sudden death in otherwise healthy adults. Because of this research, the Chisholm lab has become a training ground for fellows in cardiovascular surgery.

Yoshio Fukui’s studies, which employ high-resolution light microscopic methods including digital fluorescence microscopy, emphasize the remarkably dynamic activities of the various cytoskeletal systems and their related proteins in living cells.

Although it had been commonly believed that the intermediate filament (IF) system serves literally only a supportive role in terms of maintaining the structure of the cell, Goldman’s research over the past 15 years has indicated otherwise.

The Goldman lab has shown that the IF system forms a continuous dynamic network linking the nuclear and cell surfaces that performs important functions ranging from maintaining cell shape to regulating nuclear structures involved in regulating gene expression and DNA replication. Abnormally functioning IF have been linked to ALS, Parkinson’s disease and muscular dystrophy.

The cell surface/extracellular matrix group consists of Lorand; Veis; Mary Hunzicker-Dunn; Jonathan Jones; Sharon Stack; and James M. Kramer.

Veis is another of the department’s celebrated researchers. He studies the regulation of growth and remodeling processes in the collagen fibril matrix, bone and dentin. Remarkably, several of Veis’s NIH grants have been funded for over 40 years.

Hunzincker-Dunn studies the cell surface-mediated signaling pathways by which reproductive hormones induce differentiation of ovarian cells. She also leads an intercampus PPG that focuses on the signaling pathways and actions of follicle-stimulating hormone. Her collaborators in this venture are Weinberg researchers Jon Levine, Fred Turek and Kelly Mayo; and Larry Jameson, M.D., Irving S. Cutter Professor and chair of medicine.

The Jones lab concentrates on interactions between epithelial cells and the extracellular matrix. They have conducted studies on cell junctions called hemidesmosomes, which Jones believes act as "signal transducers" between the connective tissue and epithelial cell layers, thereby influencing epithelial gene expression. His lab group also studies surface factors that promote endothelial cells to form new blood vessels, and he directs a PPG that is studying cell alterations in oral cancer. The PPG co-investigators are Goldman, Stack and Kathleen Green, Joseph L. Mayberry Professor of Pathology.

Stack’s research focuses on the molecular mechanisms producing oral cancer and the regulatory mechanisms involved in the development of ovarian cancer. In particular, she investigates the mechanisms controlling the transition of normal cells to malignant cells capable of migrating from their normal locations to form tumors in other tissues.

Kramer studies the functions of collagen, one of the major components of the extracellular matrix. He heads up a team of researchers known affectionately as the "worm group" because they study the nematode Caenorhabditis elegans. The simplicity of this worm’s systems makes it a powerful model for molecular genetic studies of extracellular matrix functions. Kramer has shown that mutations in the genes that code for collagen in C. elegans basement membranes cause embryonic death and are similar to those in humans with Alport’s syndrome.

The group focusing on molecular mechanisms and the nucleus includes Stephen Adam, Sui Huang, Carolyn L. Jahn and Richard C. Scarpulla.

Adam studies the regulation of the transport of molecules in and out of the nucleus. He developed a biochemical assay for quantifying the movement of materials into the nucleus, now used in laboratories all over the world. His most recent studies involve a genetic approach to understanding the function and regulation of nuclear transport proteins known as the importins. These proteins play a critical role in signal transduction and the transport of gene regulators or transcription factors into the nucleus.

Huang is investigating the nuclear mechanisms underlying the processing of RNA, particularly the perinucleolar compartment — a unique nuclear structure she discovered — which is present primarily in cancer cells. She and her lab group, in collaboration with researchers at The Robert H. Lurie Cancer Comprehensive Cancer Center of Northwestern University, have been studying the prevalence of this structure in breast cancer to determine whether the presence of this nuclear structure can be used as a diagnostic indicator of malignancy.

Jahn uses several types of ciliated protozoa to study the mechanisms responsible for gene rearrangements, a phenomenon found to be associated with a number of human diseases, including birth defects and cancer. Recently she has also been collaborating with Doug Engel on the Evanston campus in genetic studies of blood cell development in the mouse.

Scarpulla’s studies center on the molecular interactions and physiological functions of proteins involved in the nuclear control of mitochondrial biogenesis. His research is widely recognized as prerequisite to understanding numerous human disorders ranging from cardiomyopathies to neuromuscular diseases that are linked to mutations in mitochondrial genes.

In the group working on Alzheimer’s disease, Binder studies the neurofibrillary tangles recognized to be a hallmark of Alzheimer’s disease. Binder was the first to discover that the tangle is made of the microtubule-associated protein, tau. Working closely with Binder is Robert Berry, who carries out biochemical studies of the self-assembly properties of tau protein in a variety of neurodegenerative diseases including Pick’s disease. In a related area, Yuri Geinisman, M.D., studies the neurobiological basis of learning and memory in aging brains.

Van Eldik is widely recognized for research on molecular mechanisms and modulation of glial cell activation during the development of Alzheimer’s disease. Her lab also studies the function of the brain nerve cell protein S100, specifically, experiments to determine whether S100 can act as a biomarker of Alzheimer’s disease and other disorders. In addition, Van Eldik plays a major role in the Drug Discovery Program and heads an NIH postdoctoral training grant in this area.

The newest member of this group is Robert Vassar who studies the role of beta-amyloid, another important marker of Alzheimer’s disease. He studies an enzyme, BACE1, known to be involved in amyloid production. Vassar also developed the BACE1 knockout mouse required for studying the biological functions of this enzyme. BACE1 has become a prime drug target for the treatment of Alzheimer’s disease.

Book Citation: Garruto, R.M. and Brown, P. Tau protein, aluminium, and Alzheimer’s

disease (Commentary). Lancet, 343: 8904 (April 23), 989, 1994.

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God understands me. why don't you?!

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The strong link between high levels of oxidative damage to cells or DNA in cells and
conditions such as Alzheimer's disease, Parkinson's disease and ALS (Lou Gehrig's
disease) motivates researchers to identify the body's enzymes that repair the
damaged DNA. Indiana University School of Medicine researchers are getting closer
to understanding the oxidative DNA damage which occurs daily in all cells of the
human body as they take in oxygen and use it for a variety of purposes. During this
process, hydroxyl free radicals are produced which attack the DNA and damage it.
Molecular biologist Mark Kelley, Ph.D., investigator in the Wells Center for Pediatric
Research at IUSM, is studying which of the body's DNA repair enzymes recognizes
various types of oxidative DNA damage and under what conditions the repair
enzymes protect cells. "We look at the healthy DNA and the damaged DNA and work
outwards. We identify the damage in the DNA, ask what enzyme recognizes it and
then we attempt to find what regulates and controls that enzyme." He and colleagues
are blocking the functions of different repair proteins to see the effect on the cells.
They are also producing excess amounts of specific DNA repair genes to see if an
increase of repair protein makes a cell healthy.

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June 2, 1998
GENE ANOMALY ISOLATED WHICH IS CAUSE OF DEMENTIA
INDIANAPOLIS—Researchers have long known that the tau protein plays a role in
various dementias, including Alzheimer’s disease. But now a select group of scientists
have isolated a mutation in the gene for tau which is the cause of a type of dementia.
Researchers at Indiana University School of Medicine and the Medical Research
Council of Great Britain will publish their findings in an upcoming issue of the
Proceedings of the National Academy of Sciences. Their research also will be
featured in an article in the June 5 issue of the magazine Science, the publication of
the American Association for the Advancement of Science.

The findings have major importance for frontotemporal dementias and may also have
implications for Alzheimer’s disease. No one knows for sure, but it is believed that
frontotemporal dementias account for 4 percent to 10 percent of all dementias.

Many Alzheimer’s disease researchers had all but abandoned the idea that the tau
protein played an integral role in some dementias, looking instead at a protein called
Beta amyloid. Genetic research in the labs of Bernardino Ghetti, M.D., of Indiana
University, and Maria Grazia Spillantini, Ph.D., of the Medical Research Council in
Cambridge, England, continued into the causes of dementia. Drs. Ghetti and
Spillantini, along with their colleagues Martin Farlow, M.D., and Jill R. Murrell, Ph.D.,
of Indiana University, and Michael Goedert, M.D., Ph.D., and Aaron Klug, Ph.D., of
the Medical Research Council, then isolated the tau anomaly.

In 1993, Dr. Farlow first became acquainted with the family whose disease led to the
discovery of the tau anomaly. The researchers studied 11 affected family members in
three generations of the family. This family’s disease is unique because it is
exclusively tau related, unlike other dementias which could have multiple causes.

In 1997, the Indiana University and Medical Research Council scientists published
their findings which identified the family’s disease as a hereditary dementia, naming it
familial multiple system tauopathy with presenile dementia (MSTD). Continued
research with the members of the family led to the identification of the anomaly in the
tau gene and the isolation of its mutations, the findings which are now being released.
“Several varieties or forms of the tau protein are normally found in the brain. What we
discovered is a difference in the amounts of some forms of the tau protein produced in
patients with MSTD,” said Dr. Ghetti. “Although we believe the actual composition of
the protein is the same in affected and non-affected individuals, the mutation in the
tau gene causes an overabundance of some forms of the tau protein.”

Tau protein is a key part of the structure of the axons, which link cells in the brain. The
axons, in effect, act like telephone lines connecting various phones or, in this case,
cells. In the tauopathy patient, tau protein no longer supports the axons, in effect
destablizing the line so it can no longer carry signals. When the system is no longer
adequately linked, phone service is disrupted or rather, brain function is diminished.
This may cause various symptoms in patients such as imbalance, memory loss,
verbal dysfunction, depression, obsessive or bizarre behavior, and ultimately
dementia.

Another breakdown in the system is caused by an abnormal amount of the tau protein
concentrating inside the cells, which causes cell death. The abnormal deposits of the
tau protein in the cells form what researchers call tau filaments.
It is possible that the mechanisms that cause MSTD and the other related
frontotemporal dementias may also contribute to the development of Alzheimer’s
disease. Researchers say that by isolating the tau gene anomaly, scientists are one
step closer to developing drugs which can act on the contributing factors of
frontotemporal dementias.

Funding for the research was provided through grants from the National Institute on
Aging and the National Institute of Neurological Diseases and Stroke, both part of the
National Institutes of Health, along with the United Kingdom Medical Research
Council, the Royal Society of London and the Metropolitan Life Foundation.
# # #
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Contact: Mary Hardin
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Page 86

INDIANAPOLIS --Alzheimer disease patients participating in the first study of the new
cholinesterase inhibitor, metrifonate, experienced improvement in their cognitive test
scores from their pre-treatment scores, an Indiana University School of Medicine
researcher reported at the 50th annual meeting of the American Academy of
Neurology.

The 1,504 patients with probable AD of mild to moderate severity participated in either
a 12-week, double-blind trial or a 26-week, double blind trial. Participants received
either a placebo, a low dose treatment of metrifonate (30-60 mg based on patient
weight), or a high dose treatment of metrifonate (60-80 mg based on weight).

According to the study's lead investigator, Martin Farlow, M.D., professor and vice
chairman for research in the Indiana University Department of Neurology, the effect of
the high dose treatment was statistically superior to that of the low dose treatment.

Patients were evaluated by ADAS-Cog, a validated, 11-item scale designed to assess
cognitive performance in areas of memory, language and the ability to follow
directions.

"This study is encouraging news for AD patients and their families," said Dr. Farlow.
"It shows metrifonate improves cognitive performance above pre-treatment levels in
patients with mild to moderate AD."

The study also showed that higher doses of metrifonate produced a more significant
improvement in cognitive performance with no increase in safety problems or decline
in tolerability.

"Peripheral cholinergic side effects did not significantly increase with the higher
dosage of metrifonate as has been seen with some of the other cholinesterase
inhibitors," Dr. Farlow added.

The study was based on four district, postive, randomized, multi-center, double-blind,
placebo-controlled trials. Metrifonate is a cholinesterase inhibitor developed by Bayer
Corporation of Connecticut.
###
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Office of Public & Media Relations
Contact: Mary Hardin

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