Researchers link the plaques and tangles of Alzheimer's disease

Alzheimer's Association
Monday, 28 July 2003

For the first time, researchers have linked the two distinctive hallmarks of Alzheimer's disease in a chain of events that leads to the death of the brain's neurons. In a study, funded in part by the Alzheimer's Association, the Northwestern University researchers showed that specific caspases, enzymes that promote apoptosis, "cell suicide", are the crucial intermediary.

In 1906 Alois Alzheimer described the plaques, aggregates of a protein fragment called beta-amyloid, and tangles, fiber tangles composed of tau, a protein that helps organize and stabilize the neuron's internal structure that characterize Alzheimer's disease. Ever since scientists have been trying to understand the relationship between these distinctive markers and the death of neurons that leads to the destruction of the brain and the dementia characteristic of Alzheimer's disease.

Recent studies have established that beta-amyloid is toxic to neurons and that beta-amyloid activates caspases. Caspases cut targeted proteins during apoptosis, promoting the death of the cell. Based on the observation that one end of the tau protein seems to block formation of tangles, Lester (Skip) I. Binder and Vincent L. Cryns, of the Feinberg School of Medicine at Northwestern University, investigated the possibility that caspases might target tau during apoptosis, removing the end fragment and causing tau to more easily form tangles.

In an article appearing in the online version of the Proceedings of the National Academy of Sciences, Binder, Cryns and colleagues established that neurons exposed to amyloid activate caspases, whose target is the tangle-blocking end of tau—a specific site called Asp421. Tau cut at Asp421 generates a short, condensed form of tau protein that rapidly promotes widespread tangles typical of Alzheimer's-affected neurons. The researchers showed that this process occurs before neuronal apoptosis.

"Tau may be the bullet fired by the amyloid gun," said Binder. "Amyloid activates the caspases that truncate tau, causing it to form tangle and promoting the death of the neuron. Finding the full pathway in the chain of events that now includes amyloid, caspases, tau tangles and neuronal death will be the next challenge."

In order to establish the action of the caspases, the researchers produced an exquisitely sensitive monoclonal antibody that recognized Tau cut at Asp421, but not the complete protein. Using this antibody, they further established that tangles in Alzheimer brain sections had the truncated form of Tau, Asp421.

"This is an important step in the right direction in our understanding of Alzheimer's disease," said W. Sue T. Griffin, member of the Alzheimer's Association medical and scientific advisory council and professor and vice chairman, Donald W. Reynolds Dept of Geriatrics, University of Arkansas Medical School. "These principal neuropathological features may by interrelated, one giving rise to the other."

This study was a collaboration of two labs and was funded by the Alzheimer's Association, the National Institutes of Health and the Howard Hughes Medical Institute. The Alzheimer's Association is the premier source of information and support for the millions of Americans with Alzheimer's. The largest private funder of Alzheimer research in the United States, the Association has committed $138 million toward research into the disease.

For more information, or to contact Alzheimer's Association, see their website at: www.alz.org