November 20, 2003

‘Suicide’ enzymes may be missing Alzheimer’s link

By Elizabeth Crown

Northwestern researchers have found that caspases, a family of protein-cutting enzymes involved in programmed cell death (apoptosis), may be a missing link in the chain of molecular events leading to Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative condition affecting an estimated 4 million Americans that causes memory loss and, ultimately, dementia. Patients with this disease have abnormal deposits (plaques) of protein fragments called amyloid-beta surrounding neurons in their brain and “tangles” of a protein called tau inside brain cells.

For years, scientists have been debating which of these two events – plaques or tangles – is the primary cause of Alzheimer’s disease. Recent studies have suggested that amyloid promotes the assembly of tau into tangles, but, until now, the actual mechanism by which this occurs was poorly understood.

In an article in the online version of the Proceedings of the National Academy of Sciences, co-senior authors Lester I. Binder and Vincent L. Cryns of the Feinberg School of Medicine report that caspases may provide a direct link between amyloid and tangles.

Because caspases were known to be activated in dying neurons in Alzheimer’s disease and to cut (cleave) tau under some circumstances, Binder and Cryns reasoned that caspases might be responsible for cleaving tau into smaller or truncated forms that are often observed in tangles.

In a collaboration between their two labs, the scientists demonstrated that exposing neurons to amyloid-beta activates caspases, which then cleave tau at a specific site (Asp421) in the tail end of the molecule. They then showed that this truncated form of tau was much more prone to forming abnormal filaments that resemble tangles, suggesting that amyloid exposure might promote tangle formation through the action of caspases on tau.

Binder is professor of cell and molecular biology and a researcher at the Cognitive Neurology and Alzheimer’s Disease Center at the Feinberg School. Cryns is assistant professor of medicine and director of the Cell Death Regulation Laboratory in the department of medicine at the Feinberg School.