Researchers Reveal Insidious Role Of A "Serpin" In Alzheimer's Disease

Alpha1-antichymotrypsin (ACT) is a serin protease inhibitor, or serpin, that normally prevents enzymes known as proteases from digesting proteins. Scientists have known for some time that production of ACT is increased in the brains of patients with Alzheimer's disease, where it is bound tightly to amyloid proteins in abnormal deposits called plaques. These plaques, along with tangled nerve fibers known as neurofibrillary tangles, are the main pathological hallmarks of Alzheimer's disease.

However, researchers have not known whether ACT counteracts or augments the build-up and possible toxicity of amyloid proteins. Some previous studies performed in cultured cells or with proteins themselves have found that ACT decreases the aggregation of amyloid proteins, while others have found the opposite effect or no effect at all.

The current study, conducted in genetically engineered mice, reveals that increased production of ACT in the brain strongly increases the build-up of amyloid proteins, which is associated with damage to brain cells within and around the plaques.

"We speculate that reducing or inhibiting the plaque-enhancing activity of ACT could help prevent the accumulation of plaques in the brain," says the lead author of the study, Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease at the UCSF-affiliated San Francisco General Hospital Medical Center, and Joseph B. Martin Distinguished Professor at UCSF.

"There's a sneakiness to this protein," Mucke says. "While the association of ACT with plaques has been known for more than ten years, the true nature of its activity in the brain has remained elusive for all this time. Our study now demonstrates that ACT insidiously increases the plaque burden in the aging brain."

The researchers report their findings in the December issue of American Journal of Pathology.

The discovery offers one more factor to consider in the ongoing efforts to prevent the formation of amyloid plaques in the brain. Researchers from Elan Pharmaceuticals recently reported that vaccinating mice with an amyloid beta peptide, a protein component of the amyloid plaque, prevented plaque deposition, and this finding has propelled the vaccine into human clinical trials.

Researchers still do not know whether the amyloid plaques or some of their components are responsible for the degeneration of brain cells and their connections, which underlie the cognitive decline in Alzheimer's disease, such as memory loss, anxiety, confusion and, ultimately, severe dementia.

Most likely, says Mucke, several factors contribute to both the brain damage and cognitive impairment in Alzheimer's disease. As the behavior of the transgenic