Surgery News

Yale researchers block transforming growth factor to clear up amyloid plaques in mice

November 10, 2015

Researchers hope the new approach may one day overcome one of the biggest obstacles to development of new dementia medications - the difficulty in finding drugs that can safely cross the blood-brain barrier.

The results of the research surprised the scientists working in the lab of Richard Flavell, senior author of the paper, chairman of the Department of Immunobiology at Yale and investigator with the Howard Hughes Medical Institute. Flavell's team originally thought that blocking the immune system molecule TGF-??(or transforming growth factor), might actually increase the buildup of amyloid plaques associated with Alzheimer's Disease

Earlier studies had shown that Alzheimer's patients tend to have elevated amounts of TGF-??, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply an attempt to quiet the inflammatory response caused by a buildup of plaque.

Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF-?? in the peripheral immune cells.

It was like a vacuum cleaner had removed the plaques," Flavell said.

When the TGF-?? pathway was interrupted in mice engineered to have Alzheimer's, the mice showed an improved ability to perform some tests, including navigating mazes when compared to mice without TGF-?? blocked. Scientists also found lower levels of other biological markers associated with the dementia.

When TGF-?? was blocked, the immune system seemed to unleash immune cells known as peripheral macrophages. The macrophages passed through the blood-brain barrier and surrounded the neurons and plaques in the brains of mice. "If results from our study in mice engineered to develop Alzheimer's-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques," said Terrence Town, lead author of the study.

The work was largely done in Flavell's lab by a team led by Town, now a research scientist with departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai Medical Center and the Maxine Dunitz Neurological Institute in Los Angeles.

Also working on the paper were Yasmina Laouar, Christopher Pittenger, and Ronald S., Duman of Yale,; Takashi Mori of Saitma University Japan; Christine A. Szekely, Johns Hopkins University and Cedars-Sinai Medical Center and Jun Tan, University of South Florida. Laouar is currently at the University of Michigan.

The work was funded with grants from the Alzheimer's Association and National Institutes of Health.

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As planned, her body was donated to science when she died at age 115. At the time, she was the world's oldest woman. Examination after death found almost no evidence of atherosclerosis (narrowing of the arteries) anywhere in her body. The brain also showed very few abnormalities??”the number of brain cells was similar to that expected in healthy people between 60 and 80 years old.

A key finding was the absence of brain abnormalities typical of Alzheimer's disease. There were almost no deposits of a substance called beta-amyloid, which are characteristic of Alzheimer's patients. The other abnormalities present, including "neurofibrillary tangles," were very mild??”too early to cause significant mental impairment.

The unique case lends new insights into the potential for preserving brain function in very elderly patients. Previous studies have found at least mild abnormalities in the brains of nearly all "cognitively normal" elderly people. As the number of people living to age 100 and beyond continues to increase, the findings suggest that deterioration of the brain is not inevitable.

In addition to the article, commentaries by Dr. Joseph L. Price of Washington University, St. Louis, Panteleimon Giannakopoulos of University Hospitals of Geneva, Switzerland and colleagues, and Drs. Kelly Del Tredici and Heiko Braak of the Institute for Clinical Neuroanatomy in Frankfurt/Main, Germany are available.

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