TANGLES (LEFT) AND PLAQUES (RIGHT)
FROM THE NATIONAL INSTITUTE ON AGING

Alzheimer's disease is characterized by two separate brain lesions: plaques and tangles. The results of a new mouse study indicate that an experimental immune therapy that targets the former can also impact the latter, so long as the disease has not progressed to an advanced state.

Alzheimer's affects nearly five million people in the U.S. and is the leading cause of dementia in the elderly here. The hallmark lesions of this neurodegenerative disorder arise from the accumulation of two proteins in the brain. Extracellular plaques result from aggregates of the amyloid beta (Ab) peptide, whereas the neurofibrillary tangles that clog neurons are made up of the tau protein.

Working with mice genetically engineered to develop both plaques and tangles, researchers from the University of California at Irvine injected Ab antibodies into the hippocampus of one-year-old individuals. The results, published in the August 5 issue of Neuron, showed that three days after injection the immune system had cleared the plaque-causing Ab from both the outside and inside of the mice brain cells. Furthermore, the tangles disappeared two days later, bolstering the "amyloid cascade hypothesis," which posits that the plaques disrupt the cells' ability to clear faulty or unneeded proteins, thereby allowing tangles to develop. Frank M. LaFerla, the head investigator, likened the behavior of the affected cells to "failing to take out your garbage." Additional support for the faulty disposal interpretation comes from the team's finding of a similar tangle reduction in mice administered a drug that interferes with the production of Ab peptide.

But the scientists determined that those tangles in which the tau protein had acquired a number of phosphate groups did not respond to Ab-based treatments. The implication is that either immune therapies based on this approach will need to be implemented early in the course of the disease-- before the tangles become resistant--or a multi-antibody approach that attacks both Ab and tau proteins will be necessary.

A clinical trial in humans of a vaccine based on Ab antibodies was halted in 2002 because 5 percent of the patients developed encephalitis. LaFerla is confident, however, that Alzheimer sufferers will one day benefit from protein cascade intervention. "If it is not the antibody treatment, then it will involve Ab-blocking drugs," he said. Clinical trials of such drugs are currently underway. --Michael Schirber