Protein linked to molecular transportation system

A protein linked to accumulation of harmful brain plaque in Alzheimer's patients has been shown in fruit flies and mice to be an important part of a molecular transportation system that moves signals and vital protein cargoes within the brain.

In addition, researchers have determined that the protein, called amyloid precursor protein (APP), can induce a biochemical process that clogs brain traffic lanes and eventually leads to neuron cell death.

"Although this is only a first step in understanding the connection between APP, axonal transport and the location where amyloid beta is produced during disease, our work offers a possible approach for the eventual design of new Alzheimer's therapies that directly target amyloid beta and APP transport," said Lawrence Goldstein, professor of cellular and molecular medicine in the University of California, San Diego (UCSD) School of Medicine.

"It is important to note that we need additional studies to determine the factors that trigger APP to produce harmful amyloid beta."

He added that all cells in the body normally produce amyloid beta but only neurons - the brain's master cells - are damaged by the protein. "That is why we asked what was special about neurons that made them susceptible to damage caused by APP."

The researchers used Drosophila, the fruit fly, to confirm the important role that APP plays in axonal trafficking. They showed that removal of APP caused a defect in the ability of neurons to transport materials through axons. In another series of experiments, when they introduced too much APP into the fruit fly, the axonal system became clogged and neurons died.

The team also used a mouse model to identify molecules moved by the transportation system - enzymes called beta-secretase (Bace) and presenilin - that also appear to be responsible for degrading APP amyloid beta. The activity appears to take place during axonal transportation of a miniscule cellular compartment that contains the APP, Bace and presenilin.

"Once amyloid beta has been generated, it is possible that the axonal pathway becomes physically blocked," Goldstein said. "We are suggesting that with this blockage, a signal is generated saying that traffic is blocked and the neuron should die."