SAN FRANCISCO, CA - January 5, 2008 - Scientists from the Gladstone Institute of Neurological Disease (GIND), UCSF, and Stanford have discovered that a certain type of collagen, collagen VI, protects brain cells against amyloid-beta (Aβ) proteins, which are widely thought to cause Alzheimer's disease (AD). While the functions of collagens in cartilage and muscle are well established, before this study it was unknown that collagen VI is made by neurons in the brain and that it can fulfill important neuroprotective functions.
The team of investigators led by GIND director Lennart Mucke, MD, reported in the current edition of the journal Nature Neuroscience, that collagen VI is increased in brain tissues of Alzheimer's patients.
"We first noticed the increase in collagen VI in the brain of AD mouse models, which inspired us to look for it in the human condition and to define its role in the disease," said Dr. Mucke.
The Gladstone team had profiled changes in gene expression using DNA microarrays, which provides an unbiased method for identifying key biological pathways. By comparing all of the genes that are active in disease and normal tissue, one can get valuable information on new pathways and potential therapeutic targets.
The researchers looked at the dentate gyrus, a specific area of the brain that is critical to memory and particularly vulnerable in AD, and compared the genes that were turned on and off in normal mice and a mouse model of AD. This analysis revealed the striking increase in collagen VI in the brains of mice that model AD.
Building on this initial finding, the team examined brain tissue from AD patients and normal non-demented humans and found that collagen VI expression was also higher in the AD patients. They further discovered that the cellular source of the collagen VI in the brain was neurons, the very cells that the disease attacks and that we all need to think and remember.
"These findings were really surprising and exciting to us because nobody knew anything about collagen VI in the brain," said Jason Cheng, MD, co-lead author of the study. "We were particularly curious whether collagen VI contributed to neuronal damage in AD or was produced as a defense mechanism against it," added Dena Dubal, MD, PhD, co-lead author of the study.
To answer this and other questions, the scientists carried out a series of informative cell culture experiments. These experiments revealed found that Aβ added to neurons grown in culture increased the expression of collagen VI and that this process involved the immune regulatory cytokine TGFβ. What is more, the team discovered that increasing the amount of collagen VI in the cultures effectively protected the neurons against Aβ toxicity.
"This striking protective effect suggests that increased neuronal production of collagen VI is an important component of the brain's defense against Aβ," said Dr. Mucke. "It made us really curious about the underlying mechanisms."
To clinch these mechanisms, Dr. Mucke's team examined the direct interactions of collagen VI with Aβ. They looked at how Aβ attacks individual neurons in cell culture. Small poisonous Aβ assemblies, called oligomers, bind strongly to vulnerable neurons in the brain, but in the presence of collagen VI, this binding was blocked. Using immunohistochemistry and atomic force microscopy, they showed that collagen VI and Aβ form large aggregates with each other that may sequester the smaller, more toxic Aβ complexes away from neurons.
"We are eager to explore how this kind of process might be enhanced therapeutically and how we can best leverage it for the development of more effective treatments for this devastating condition," said Dr. Dubal.
Other members of the research team were Gladstone's Irene Cheng, Daniel Kim, and Gui-Qiu Yu. Ina Tesseur and Tony Wyss-Coray of Stanford University and Paolo Bonaldo of the University of Padova, Italy also contributed to this study. The research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, and the Larry L. Hillblom Foundation.
About the Gladstone Institutes
The J. David Gladstone Institutes, an independent, non-profit biomedical research organization affiliated with the University of California, San Francisco (UCSF), is dedicated to the health and welfare of humankind through research into the causes and prevention of some of the world's most devastating diseases. Gladstone is comprised of the Gladstone Institute of Cardiovascular Disease, the Gladstone Institute of Virology and Immunology and the Gladstone Institute of Neurological Disease. More information can be found at www.gladstone.ucsf.edu.