Scientists from the Gladstone Institute of Neurological Disease 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.

The functions of collagens (collagen is the main protein of connective tissue) in cartilage and muscle are well established, but before this study it was unknown that collagen VI is manufactured by neurons in the brain and that it can fulfill important neuroprotective functions.

The team of researchers led by Lennart Mucke, MD, reported in a recent 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 Alzheimer's 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 (microarrays allow scientists to analyze expression of many genes in a single experiment quickly and efficiently), 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 part of the hippocampal formation and a specific area of the brain that is critical to memory and particularly vulnerable in Alzheimer's, and compared the genes that were turned on and off in normal mice and a mouse model of Alzheimer's. This analysis revealed the striking increase in collagen VI in the brains of mice that model Alzheimer's.

Building on this initial finding, the team examined brain tissue from Alzheimer's patients and normal non-demented humans and found that collagen VI expression was also higher in the Alzheimer's 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 Alzheimer's 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 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, the researchers 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 (the localization of proteins in tissue sections by the use of visualized marker agents) and atomic force microscopy (a high-resolution scanning probe microscope with a resolution of fractions of a nanometer), 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.