Molecules trigger inflammation in Alzheimer disease

April 29, 2003

The main pathological signature of Alzheimer disease (AD), which causes progressive memory loss in its victims, is plaques in the brain. Currently, massive research efforts are geared toward eliminating these plaques.

In a new study published in the April issue of the Journal of Neuroscience, researchers at the Alzheimer Research Laboratory at Case Western Reserve University School of Medicine report finding the molecules that play a critical role in making the brain think it is under attack from these plaques, triggering immune cells in the brain. The inflammation mediated by these cells speeds up the debilitating consequences of AD. With the discovery of these molecules, researchers say new therapies could be devised aimed at blocking their action to slow down progression of AD.

From previous studies looking at people with rheumatoid arthritis, scientists know that people on non-steroidal, anti-inflammatory drugs, such as ibuprofen, have a lower incidence of AD. Gary Landreth, Ph.D., professor of neurosciences at CWRU, and his team, are searching for why this happens.

He says the anti-inflammatory drugs turn down inflammation caused by the brain's immune cells, called microglial cells. These cells detect plaques, made of a protein called beta amyloid, as a foreign substance and, just as white blood cells in the blood would try to mount an attack around a cut in the skin to prevent infection, the microglial cells seemingly gear up for an attack against the amyloid invaders. However, for reasons unknown, the microglial do not follow through on the attack, but remain inflamed.

"When microglia undergo this activation, they secrete a large number of very nasty things," says Landreth. "Over the long term, it's these inflammatory products of microglia that play a significant role in killing neurons." The death of neurons leads to the loss of memories and brain function.

According to Landreth, if researchers could block the interaction of the microglia with the amyloid, then the microglia would not detect the amyloid and there would be no inflammation. Even when left with beta amyloid plaque in their brains, AD suffers would have a slower progression of the disease, according to Landreth.

His lab set out to find out how microglial cells detect the amyloid. A graduate student in his lab and lead author of the study, Maria E. Bamberger, found that the microglial cells use an ensemble of at least four different receptor proteins to bind to the amyloid. Each one of these receptor proteins act together at the same time to drive the inflammation.

"This fundamentally changes how people think about how the amyloid plaques provoke microglial activation. There were a number of competing theories with other receptor molecules that people suggested had been true, but this study essentially challenges those hypotheses," says Landreth.

The new discovery allows researchers to devise new therapies against the inflammation. "If we block any one of these receptors, we would block the inflammatory response," says Landreth. "This presents new targets for new therapies to treat Alzheimer's disease," he says.
Other authors on the paper are Meera E. Harris, CWRU; Douglas R. McDonald, Children's Hospital, Boston, and Jens Husemann, Columbia University College of Physicians and Surgeons, New York. The study was supported by the National Institutes of Health, the Blanchette Hooker Rockefeller Foundation, and the Coins for Alzheimer's Research Trust Fund of Rotary International.

Case Western Reserve University

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