Plaque-forming protein seen in Alzheimer's linked to clogged brain transportation system

December 05, 2001

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.

The findings are the first scientific data that describe the transport role of APP and that offer a new hypothesis linking the protein's cellular trafficking function to the formation of harmful plaque deposits called amyloid beta in the brains of Alzheimer's victims.

Conducted in the lab of senior author Lawrence S.B. Goldstein, Ph.D., a Howard Hughes Medical Institute investigator and professor of cellular and molecular medicine in the University of California, San Diego (UCSD) School of Medicine, the studies were published in the Nov. 8, 2001 issue of the journal Neuron and the Dec. 6, 2001 issue of the journal Nature.

"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," Goldstein said. "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's why we asked what was special about neurons that made them susceptible to damage caused by APP."

Although scientists have known that APP generates the plaque-forming amyloid-beta, they have not understood how the protein operates in mammals, or the physical location where APP generates amyloid-beta.

In research first published in Neuron in November 2000, the Goldstein team described the first evidence for APP's new role by noting that a biochemical reaction takes place between APP and an enzyme that is crucial for the movement of signals and other materials through axons, the threadlike projections of the central nervous system which enable the neuron to transmit signals rapidly over relatively long distances in the body.

In the November 8, 2001 issue of Neuron, 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.

In their most recent Nature article, the team 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're suggesting that with this blockage, a signal is generated saying that traffic is blocked and the neuron should die."
In addition to Goldstein, the other author of the November 8 Neuron paper was Shermali Gunawardena, Ph.D., a post doctoral fellow in the UCSD Department of Cellular and Molecular Medicine.

Additional authors of the Nature paper were post doctoral fellows Adeela Kamal, Ph.D. and Angels Almenar-Queralt, Ph.D., and Elizabeth A. Roberts, M.A., research technician, UCSD Department of Cellular and Molecular Medicine; and James F. LeBlanc, Ph.D., Ciphergen Biosystems, Inc., Freemont, CA.

The studies were funded by the National Institutes of Health, the Wills Foundation, and Howard Hughes Medical Institute.

University of California - San Diego

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