October 6, 2000

Study finds key link between Alzheimer's genes and cellular defect

An MGH-based research team has linked two cellular abnormalities associated with early-onset Alzheimer's disease – mutations in genes for proteins called presenilins and an altered handling of calcium inside cells. The team has tied a specific calcium pathway to the production of amyloid-beta42 (A-beta42), the sticky protein fragments that make up the plaques found in the brains of people with the disease. The findings identify a new target for drugs that may prevent or treat the devastating disease.

In a paper in the September issue of Neuron, the scientists from the MGH Genetics and Aging Unit and colleagues from other institutions report that the presenilins appear to control a process that regulates the level of calcium in a cellular compartment called the endoplasmic reticulum and that presenilin mutations known to be associated with inherited Alzheimer's disease slow down this regulatory process. They also show that inhibiting this particular calcium pathway – called capacitative calcium entry – increases production of A-beta42.

"We have found the molecular basis of the altered calcium metabolism previously observed in neurons expressing Alzheimer's-associated versions of presenilin," says Tae-Wan Kim, PhD, the paper's senior author. "We also identified a link between a specific calcium influx pathway and aberrant, presenilin-mediated processing of the amyloid precursor protein." Kim, who had been a member of the MGH Genetics and Aging Unit, recently joined the faculty at Columbia University College of Physicians and Surgeons.

Rudolph Tanzi, PhD, at right, director of the MGH Genetics and Aging Unit and a co-author of the Neuron paper, adds: "Our work predicts that, if you could develop a drug that stimulates this specific calcium pathway, you could lower levels of A-beta42, which is the name of the game in Alzheimer's disease drug therapy development."

Other MGH co-authors of the Neuron paper are Tallessyn Grenfell, Eunju Pack-Chung, Giuseppina Tesco, MD, and Aleister Saunders, PhD, of the MGH Genetics and Aging Unit.