Transthyretin: A Neural Protein that Stops the Progression of Alzheimer's Disease

Jeffrey A. Johnson, Ph.D.
University of Wisconsin, Madison
R01ES08089 and R01ES10042

Background: Named for Dr. Alois Alzheimer, Alzheimer's disease (AD) is characterized by the presence of protein plaques and tangles of fibers in brain tissue. As many as 4.5 million Americans suffer from AD, which usually begins after age 60, and the risk of developing the disease goes up with age. About 5 percent of men and women ages 65 to 74 have AD, and nearly half of those age 85 and older may have the disease.

Other brain abnormalities in people with AD include the death of nerve cells in specific areas of the brain that are vital to memory and other mental abilities. There also are lower levels of some of the chemicals in the brain that carry messages back and forth between nerve cells. AD may impair thinking and memory by disrupting these messages. A recent study by NIEHS grantee Dr. Jeffrey Johnson of the University of Wisconsin has identified a protein known as transthyretin that blocks the effects of beta-amyloid proteins which lead to the formation of the protein plaques.

Advance: Using a transgenic mouse which had defective genes from early-onset AD patients inserted into its DNA, Dr. Johnson noticed that although these mice had high levels of beta-amyloid protein, they did not exhibit any neurodegenerative symptoms. Further investigations led the research team to discover that these mice also were producing high levels of transthyretin. When the mice were given antibodies that prevented transthyretin from interacting with the beta-amyloid protein, the mice showed typical brain cell death. In vitro studies of human brain cells treated with transthyretin and beta-amyloid showed minimal amounts of cell death, confirming the results seen in the mice.

Implications: These studies show that transthyretin can block the progression of AD by inhibiting the effects of beta-amyloid protein. This discovery suggests that it may be possible to develop a drug that increases the production of tranthyretin and thus protects people at risk for AD such as those with a genetic predisposition. The findings may also improve the detection of environmental agents that may play a role in the development of AD by allowing scientists to determine which of these agents upsets the balance between transthyretin and beta-amyloid proteins.

Citation: Stein TD, Anders NJ, DeCarli C, Chan SL, Mattson MP, Johnson JA. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis. J Neurosci. 2004 Sep 1;24(35):7707-17.