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Brain cell activity regulates Alzheimer’s protein​

February 25, 2014
By Michael C. Purdy

Increased brain cell activity boosts brain fluid levels of a protein linked to Alzheimer’s disease, according to new research from scientists at Washington University School of Medicine in St. Louis.

Tau protein is the main component of neurofibrillary tangles, one of the hallmarks of Alzheimer’s disease. It has been linked to other neurodegenerative disorders, including frontotemporal dementia, supranuclear palsy and corticobasal degeneration.


“Healthy brain cells normally release tau into the cerebrospinal fluid and the interstitial fluid that surrounds them, but this is the first time we’ve linked that release in living animals to brain cell activity,” said senior author David M. Holtzman, MD. “Understanding this link should help advance our efforts to treat Alzheimer’s and other neurodegenerative disorders associated with the tau protein.

The study appears online in The Journal of Experimental Medicine.

Tau protein stabilizes microtubules, which are long columns that transport supplies from the center of the cell to the distant ends of the cell’s branches. Some tau in the cell is not bound to microtubules. This tau can become altered and clump together inside brain cells, forming structures called tangles. Scientists have tracked the spread of these clumps through brain networks in animal models.

“In Alzheimer’s disease, you first see clumps of tau in a region called the entorhinal cortex, and then in the hippocampus, and it continues to spread through the brain in a regular pattern,” said Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “In another disorder, supranuclear palsy, tau clumps first appear in the brain stem and then spread to regions that the brain stem projects to.”

These regular patterns of tau spread through brain networks have led scientists to speculate that dysfunctional tau travels to different brain regions via synapses — the areas where individual nerve cells communicate with each other.

Holtzman’s results support this hypothesis, showing that when nerve cells “talk” to each other, tau levels go up in the fluids between those cells, suggesting that brain cells are secreting tau when they send signals.

So far, the researchers only have been able to measure single copies of tau in brain fluid, not the tau clumps. They are looking for a way to detect the clumps. If brain cells can secrete and take in clumps of tau, the scientists believe, these clumps may cause previously normal tau in the receiving cell to become corrupted, fostering the spread of a form of tau involved in disease.

“We also want to know whether brain cells are secreting tau as waste or if tau has a function to perform outside the cell,” Holtzman said. “For example, there have been hints that tau may modulate how easy or difficult it is to get brain cells to communicate with each other.”

This study was supported by the Tau Consortium and the Japan Society for the Promotion of Science.
Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgräfe K, Mandelkow E-M, Holtzman DM. Neuronal activity regulates extracellular tau in vivo. The Journal of Experimental Medicine, published online Feb. 18, 2014. DOI: 10.1084/jem.20131685
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Academy of Science of St. Louis honors four WUSTL researchers

January 14, 2014
By Michael C. Purdy and Beth Miller

Four Washington University in St. Louis researchers are being honored as outstanding scientists by the Academy of Science of St. Louis.

Each year, the academy seeks nominations of outstanding women and men in science, engineering and technology who are known worldwide for their scientific contributions to research, industry and quality of life. Those recognized also have a record of excellence in communicating with the public and/or mentoring colleagues.

John E. Heuser, MD, professor of cell biology and physiology at the School of Medicine, will receive the Academy of Science’s Peter H. Raven Lifetime Achievement Award; David Holtzman, MD, the head of the Department of Neurology, will be honored with the Fellows Award; Caitlin Kelleher, PhD, the Hugo F. & Ina Champ Urbauer Career Development Associate Professor, will receive the Innovation Award; and Lihong Wang, PhD, the Gene K. Beare Distinguished Professor of Biomedical Engineering, will be recognized with the James B. Eads Award.

Heuser, MD, emeritus professor of cell biology and biophysics, pioneered a technique for imaging cells and molecules in the electron microscope that he calls the “quick-freeze deep-etch” procedure. The process has allowed him and his colleagues to take highly detailed pictures of rapid events, including the communication that occurs between nerve cells, the uptake and secretion of materials into and out of cells, and the rapid movements of cells ranging from contracting muscle cells to swimming sperm.

He continues to use his approach, in conjunction with other advanced electron microscope techniques, to provide unique and insightful 3-D views, known as “Heusergrams,” of membranes and molecules in a wide variety of biological contexts, including nerves, muscles, glands, blood, skin and bone. Heuser recently patented an update of the original machine.

Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and a professor of developmental biology, specializes in investigating the molecular mechanisms that cause Alzheimer’s disease and developing new treatments. His team played a leading role in showing how dangerous amounts of a protein called amyloid-beta (ABeta) begin to accumulate in the brain many years before symptoms arise.

Holtzman and his colleagues also have made important contributions to the search for markers of pre-symptomatic disease, research that is expected to help clinicians one day start treatment for Alzheimer’s disease prior to dementia. For example, they recently established a strong link between sleep disruption and Alzheimer’s risk.

Together with collaborators at Eli Lilly and Co., Holtzman has identified antibodies that can decrease amyloid plaques over months in mice. One of those antibodies is being tested in clinical trials involving patients with inherited forms of Alzheimer’s disease.

Kelleher will receive the Innovation Award, which recognizes a scientist or engineer, age 40 or younger, who has demonstrated exceptional potential for future accomplishments in science, engineering or technology.

Kelleher’s research centers on “democratizing” computer programming to make it accessible for everyone.

As a graduate student at Carnegie Mellon University, Kelleher created a programming system, called Storytelling Alice, which presented programming as a means to the end of creating animated stories. She found that Storytelling Alice greatly increased interest in programming. But she also found that many children in the United States don’t have access to a computer science class before college.

When she joined the WUSTL faculty in 2007, Kelleher began work on Looking Glass, a programming environment that explores a variety of mechanisms to support kids learning to program without the support of a teacher or classroom setting. Users write programs to create animated stories that they can share through an online community, where they become potential learning aids.

Kelleher and her group also have created a version of Looking Glass that enables physical and occupational therapists to create games for stroke rehabilitation.

Wang will receive the James B. Eads Award, which recognizes a distinguished individual for outstanding achievement in engineering or technology.
Wang and his lab were the founders of a type of medical imaging that gives physicians a new look at the body’s internal organs, publishing the first paper on the technique in 2003. Called functional photoacoustic tomography, the technique relies on light and sound to create detailed, color pictures of tumors deep inside the body and may eventually help doctors diagnose cancer earlier than is now possible and to more precisely monitor the effects of cancer treatment — all without the radiation involved in X-rays and CT scans or the expense of MRIs.

A leading researcher on new methods of cancer imaging, Wang has received more than 30 research grants as the principal investigator with a cumulative budget of more than $40 million. In 2013, Wang received a Transformative Research Award from the National Institutes of Health.

The Academy of Science of St. Louis aims to foster the advancement of science and encouragement of public interest in and understanding of the sciences. The awards will be given April 9 at the Chase Park Plaza Hotel.

Holtzman, Bateman win Chancellor’s Innovation Award

December 3, 2013
By Michael C. Purdy

David M. Holtzman, MD, and Randall J. Bateman, MD, have been chosen as co-recipients of the Chancellor’s Award for Innovation and Entrepreneurship at Washington University in St. Louis.

Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, and Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology, will be presented with the honor at the Faculty Achievement Awards ceremony Saturday, Dec. 7, in Simon Hall.

Also to be presented at the ceremony are 2013 faculty achievement awards for Richard H. Gelberman, MD, the Fred C. Reynolds Professor and head of the Department of Orthopaedic Surgery, and James V. Wertsch, PhD, vice chancellor for international affairs, director of the McDonnell International Scholars Academy and the Marshall S. Snow Professor in Arts & Sciences.

Gelberman will receive the Carl and Gerty Cori Faculty Achievement Award, while Wertsch will receive the Arthur Holly Compton Faculty Achievement Award. Visit here to read an earlier article about their achievements.

The Chancellor’s Award for Innovation and Entrepreneurship is given on an occasional basis to faculty members whose research has led to the successful development of ideas or businesses that have brought great benefit to others.

“For years, David Holtzman and Randall Bateman have been making prominent and pioneering contributions not only to the early diagnosis and treatment of Alzheimer’s disease but also to our basic understanding of the causes of this disorder,” said Chancellor Mark S. Wrighton. “Their work and that of their colleagues at the Knight Alzheimer’s Disease Research Center (ADRC) has given the world new hope of one day slowing or stopping this devastating condition.”

Bateman’s and Holtzman’s accomplishments include the development of stable isotope-linked kinetics (SILK), which involves giving human research participants a slightly altered form of one of the amino acids the body uses to make proteins.

The alteration has no effect on the chemistry of the amino acid, but scientists can detect its presence in samples taken from spinal fluid and blood. Through monitoring of the presence of the amino acid in proteins of interest, scientists can track how quickly these proteins are made in and cleared from the central nervous system. Assessing these rates helps scientists understand what is going wrong and look for changes in these problems during clinical trials of new treatments.

To make SILK available to the research community as well as to the biotechnology and pharmaceutical industries, Holtzman and Bateman co-founded a company called C2N Diagnostics in 2007.

Holtzman is a leading expert in researching the underlying mechanisms that lead to Alzheimer’s disease to improve diagnosis and treatment. His research team works with mouse models of Alzheimer’s and with the Knight ADRC. Based on those insights, his lab has developed new treatments for Alzheimer’s.

Bateman is principal investigator of the Dominantly Inherited Alzheimer’s Network Trials Unit, which recently began treating participants who have inherited forms of the disease prior to the onset of symptoms.

Holtzman has five U.S. patents issued and 10 pending. Bateman has two U.S. patents issued and seven pending.

Both are physicians at Barnes-Jewish Hospital.

Holtzman earned his bachelor’s and medical degrees from Northwestern University. He completed an internship, residency and postdoctoral fellowship at the University of California, San Francisco, before joining the faculty at Washington University in 1994.

Bateman earned bachelor’s degrees from Washington University in biology and electrical engineering. He earned his MD with special emphasis in neuroscience at Case Western Reserve University School of Medicine. He completed a medical internship at Barnes-Jewish Hospital, followed by a neurology residency at Washington University. He became a member of the faculty in 2005.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.