Scientists Find Protein May Protect Against Alzheimer's Disease

By Renee Twombly

Scientists at The Scripps Research Institute report that a protein capable of producing what has been called "Alzheimer's of the heart" has been found to protect against development of Alzheimer's disease in the brain in rodent models.

The scientists say the findings suggest that the protein, transthyretin (TTR), could represent a powerful natural defense against development of Alzheimer's disease in humans, a defense that diminishes as people grow older. If so, TTR-based therapy might help treat or prevent the disorder.

The findings are being published in this week's early online edition of the Proceedings of the National Academy of Sciences (PNAS).

"This is a very surprising observation," said Professor Joel Buxbaum of the Scripps Research Department of Molecular and Experimental Medicine, first author of the paper. "We have genetic and biochemical evidence that a protein that makes tissue compromising amyloid deposits in one circumstance can be an amyloid inhibitor in another."

Buxbaum has long studied cardiac amyloidoses, disorders in which varied mutations in the gene that produces TTR lead to production of misfolded proteins that stick together into tiny thread-like aggregates. These insoluble molecular clumps deposit in the heart, leading to cardiac failure. Buxbaum and his colleagues have characterized several of these TTR mutations, including the form associated with early, aggressive heart disease.

This same process of amyloid formation occurs in the brain of people with Alzheimer's disease, but, in that disorder, the proteins that stick together are amyloid-beta (Aβ), proteins that do not affect the heart. TTR protein, which is made in the liver to transport vitamin A and the thyroid hormone through the bloodstream, has rarely been sighted in brain tissue. But there have been scattered research studies over the past 15 years that have found TTR can bind with Aβ, thereby preventing Aβ molecules from clumping together.

Even if these two proteins do stick together, preventing further deposition, Buxbaum thought it was improbable that TTR could protect against plaque formation in the brain. "It doesn't make sense for a lot of reasons," he said. "One is that TTR is produced in very limited quantities in the brain while there is a lot of Aβ around, so it is difficult to imagine how TTR could stop a build-up of Aβ. The other is that it would just be biologically ironic that a protein with the potential of forming heart plaque can prevent development of brain plaque."

TTR Stalled Development of Disease

To settle the question, Buxbaum and his team designed a series of experiments to find out what would happen in a mouse model of Alzheimer's disease if TTR protein levels were manipulated. They used APP23 transgenic mice that develop brain plaque and cognitive deficits because they carry a gene encoding a dominant human Alzheimer's mutation, and they bred these APP23 mice to mice that over-expressed human TTR (hTTR) protein or to mice missing both copies of their TTR genes (mTTR).

They found that cognitive function in APP23/hTTR mice was substantially improved compared to APP23 mice. "Carrying the hTTR gene was associated with less severe Alzheimer-like brain pathology and smaller amounts of Aβ compared to what was found in the brains of control APP23 mice," Buxbaum said. "The only way to explain this is that hTTR protein bound to Aβ either before or when it was most toxic."

Conversely, APP23 mice born without any endogenous (natural) TTR protein showed evidence of increased Aβ deposition compared to animals with normal mTTR genes. Usually APP23 mice develop Alzheimer's disease when they are nine to ten months of age, but a majority of mice in this experiment had brain deposits at about five months, the researchers report.

"When we got rid of the natural TTR protein in these mice, Alzheimer's disease occurred earlier and was much worse, and when we added back human TTR protein, the disease improved," Buxbaum said.

"The simplest interpretation of our findings is that TTR binds Aβ in a manner that prevents both toxicity and plaque formation, presumably by interfering with aggregation of the kinds of Aβ that is most likely to stick together and cause neurological and behavioral deficits in our experimental mice," he said. "These studies suggest that a similar relationship may exist in the human brain, and this is not what we expected."

It may be that human brain plaque formation only occurs when there is insufficient TTR available to inhibit aggregation, such as late in life, the researchers say. If that is the case, it may be possible to increase TTR production in the brain or to supplement falling TTR production with a look-alike agent, Buxbaum said.

TTR may also have other responsibilities in the brain. In a separate experiment, researchers found that normal mice—those not programmed to develop Alzheimer's disease—that lacked mTTR gene expression displayed a defect in spatial learning. "This confirms a recently reported observation that mTTR has a behavioral function independent of its interaction with Aβ," Buxbaum said.

"Many proteins have numerous functions, and this work leads us to think that the most important role of TTR is in the brain," he continued. "Its job as a transport vehicle in the blood may just be something else that it does, and this fundamentally alters how we think about this gene."

Other authors of the paper, "Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity," are Pritam Das and Todd Golde of the Mayo Clinic College of Medicine (Jacksonville, FL), Eliezer Masliah of the University of California, San Diego, and Zhengyi Ye, Natalia Reixach, Linsey Friske, Coree Levy, Amanda Roberts, and Tamas Bartfai of The Scripps Research Institute. See http://www.pnas.org/cgi/content/abstract/0712197105v1.

The research was supported by the National Institutes of Health, the W.M. Keck Foundation, the Skaggs Foundation, the Fidelity Foundation and The Stein Fund.

Send comments to: mikaono[at]scripps.edu

"This is a very surprising observation."

—Joel Buxbaum