Researchers link the plaques and tangles of Alzheimer's disease

July 28, 2003

For the first time, researchers have linked the two distinctive hallmarks of Alzheimer's disease (AD) 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, Northwestern University researchers showed that caspases, enzymes that promote apoptosis, "cell suicide," are a crucial intermediary.

In 1906 Alois Alzheimer described the two characteristics of Alzheimer's disease, the plaques, aggregates of a protein fragment called beta-amyloid, and tangles, abnormal filaments composed of tau, a protein that normally helps organize and stabilize the neuron's internal structure but becomes "tangled" in AD. 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 AD.

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 inhibit the formation of tangles in vitro, Lester 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, co-senior authors Binder and Cryns and their colleagues established that neurons exposed to amyloid activate caspases, which then cut tau at its tangle-blocking end--a specific site called Asp421. Tau cut at Asp421 generates a shorter, truncated form of tau protein that rapidly assembles into abnormal filaments which are similar to the tangles found in 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 tangles and likely 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 caspase-truncated form of tau.

"Establishing such a link between tau tangles and b-amyloid plaques, is a step in the right direction in our understanding of Alzheimer's disease," said Sue Griffin, member of the Alzheimer's Association Medical and Scientific Advisory Council, professor of the Donald W. Reynolds Geriatrics at the University of Arkansas for Medical Sciences and director of research at the Geriatric Research, Education, Clinical Center at the Veterans Administration Medical Center. "This study suggests that these principle neuropathological features of Alzheimer's disease are 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 nearly $140 million toward research into the disease.
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Alzheimer's Association

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