New Study Produces Alzheimer's Surprise

Plaque Deposits Significantly Reduced

...It all started when researchers interrupted a signaling pathway in certain immune system cells in laboratory mice.

The result was opposite the effect researchers expected, but it has opened the possibility of a new approach to treating Alzheimer's disease.

Immune systems cells from outside the brain targeted the sticky plaque buildup that occurs in the brains of patients with Alzheimer's disease.

In the animal study, these cells were attracted to the plaque and able to cross the blood-brain barrier. 

That's a natural barrier that prevents most substances from entering the brain from the bloodstream.

The good news is that plaque deposits were significantly reduced and mice performed better on behavioral tests.

"Attempts to develop therapies for Alzheimer's disease have been difficult because most rely on getting a therapeutic molecule or antibody across the blood-brain barrier. 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, Ph.D., first and co-corresponding author of the article.

Town is a research scientist with the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai Medical Center and with Cedars-Sinai's Maxine Dunitz Neurosurgical Institute. He performed the majority of this work at the Yale University School of Medicine in the laboratory of Richard Flavell, Ph.D., senior and co-corresponding author on the article, Sterling professor and chairman of the Department of Immunobiology and Howard Hughes Medical Institute investigator at the Yale University School of Medicine.

Amyloid plaques, composed of a protein called amyloid-fO (AfO), are thought to damage brain nerve cells (neurons) and stimulate a response in nearby inflammatory cells called microglia. Theoretically, Alzheimer's might be treated by somehow preventing or removing the plaque buildup and calming the inflammation.

"Our group has been working at the interface of the immune system and the brain," said Town. "We believe the kind of chronic, low-level inflammatory response that we see in Alzheimer's disease is deleterious, and we'd like to find a way to turn it around into a therapeutic modality."

Attempts to stimulate a beneficial immune response have been limited not only by access -- the blood-brain barrier -- but also by the fact that the brain is an "immune privileged" environment, not conducive to a strong immune response from microglia and other brain-resident immune cells.

Earlier studies have shown that an immunosuppressive molecule called transforming growth factor-fO (TGF-fO) is upregulated in the brains of patients with Alzheimer's disease. This upregulation may represent the brain's attempt to return to normalcy by quieting the immune response around the amyloid plaques. Town and his colleagues used genetically engineered mice to study the effects in the brain of blocking the TGF-fO molecule on immune cells outside the brain (peripheral macrophages).

"If these experimental animals are representative of the clinical syndrome of Alzheimer's disease, we may have a therapeutic target that we did not have before -- TGF-fO on these peripheral macrophages," said Jun Tan, M.D., Ph.D. co-author of the study, professor and Robert A. Silver chair in developmental neurobiology at the University of South Florida.

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New Study Produces Alzheimer's Surprise