Does sAPP Zap Neurons in Alzheimer's?

A protein that amasses in the brains of patients with Alzheimer's disease may help cause the massive die-off of neurons by triggering a destructive inflammatory response, a study to appear in tomorrow's issue of Nature suggests. The finding could finally explain how one of the disease's hallmarks--deposits of what's known as amyloid precursor protein--contributes to the symptoms. It could also explain the success of anti-inflammatory drugs in delaying the onset and progression of Alzheimer's.

Hoping to learn what causes the brain inflammation seen in Alzheimer's, Steven Barger, a cellular neurobiologist at the University of Arkansas for Medical Sciences, Little Rock, decided to test whether a secreted form of the amyloid precursor protein, called sAPP, might trigger the reaction. Barger and his student Ashley Harman added sAPP to cultured neurons and microglia--cells that help serve as the brain's immune system. The microglia enlarged and began to pump out toxins as part of the inflammatory response.

After one day, 63% of the neurons had died, compared to only 7% of neurons in a control. The researchers also found another tie-in to human Alzheimer's: When the sAPP was pre-treated with apolipoprotein E3, the microglia did not activate. But apolipoprotein E4--a variant associated with higher risk of developing Alzheimer's--did not provide this protection.

"The bottom line is quite clear," says Zaven Khachaturian, a neurobiologist and director of the Alzheimer Association's Ronald and Nancy Reagan Research Institute, "sAPP plays an important role in the disease." But nagging questions remain, he says. "At what stage in the disease process does it come into the picture and where does it fit in the cascade of events?"