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Study Hints at “Missing Link” Connecting Plaques and Tangles

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Northwestern University researchers have found a molecular mechanism linking beta-amyloid, the chief component of plaques, and tau, primary component of tangles. Ever since German neuropsychiatrist Alois Alzheimer first identified brain plaques and tangles as the hallmarks of Alzheimer’s disease in 1906, scientists have sought to understand the relationship between the lesions and debated which one initiates the insidious process that eventually destroys nerve cells throughout the brain.

In work supported in part by the Alzheimer’s Association and appearing in the July 28 on-line edition of the Proceedings of the National Academy of Sciences, Vincent L. Cryns, MD, and Lester I.

Binder, PhD, report that a family of enzymes called caspases may be the missing link. Cryns, Binder, and colleagues describe a molecular scenario in which beta-amyloid activates caspases and the caspases in turn clip one end off tau. Loss of that piece makes tau much more prone to form tangles.

“Tau may be the bullet fired by the amyloid gun,” says Binder. “Amyloid activates the caspases that truncate tau, causing it to form tangles and likely promoting the death of the nerve cell. Finding the full pathway in the chain of events that now includes amyloid, caspases, tau tangles, and nerve cell death will be the next challenge.”

Binder and Cryns focused on caspases because these enzymes play a role in programmed cell death (apoptosis), a sequence of orderly biochemical steps for eliminating diseased cells from the body. Researchers suspect that disruptions in programmed cell death may play a role in cancer, Alzheimer’s, and other diseases. Caspases have also been shown to cut tau under some circumstances, and scientists have observed that tangles often contain a shortened form of tau.

In laboratory work, Cryns and Binder showed that exposing cultures of nerve cells to beta-amyloid activates caspases, which clip tau at a highly specific site called Asp421. This shortened tau then forms tangle-like structures. The researchers brought their discovery closer to real-world biology by manufacturing an antibody capable of attaching only to tau clipped at Asp421. Using this antibody, they showed that the tangles in brain tissue samples from individuals with Alzheimer’s disease contain tau clipped at the caspase-specific Asp421 site.

“Establishing this link between plaques and tangles is a step in the right direction in our understanding of Alzheimer’s disease,” says Sue Griffin, PhD, member of the Alzheimer’s Association Medical and Scientific Advisory Council and professor at the Donald W. Reynolds Center on Aging at the University of Arkansas for Medical Sciences as well as director of research at the Geriatric Research, Education, and Clinical Center at the Veterans Administration Medical Center in Little Rock. “This study suggests that these principal pathological features of Alzheimer’s disease are interrelated.”

This work received funding from the National Institutes of Health and the Howard Hughes Medical Institute in addition to the Alzheimer’s Association

Source: The Alzheimer’s Association. Online at www.alz.org.

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