If you imagine the cell body as a 50-foot room, the axon could extend up to 200 miles away, he said. The cell would have to ship cargo along rather narrow 20-foot pipes and keep track of everything that is happening along the route.
When something goes wrong with this transport process, the cell often cannot cope and sends out a distress signal that initiates cell death. Goldstein and his colleagues have studied this process and conclude that APP may be involved in a signaling process that leads to cell death when nerve cells are damaged.
Furthermore, the scientists discovered that two other key Alzheimers-disease-related proteins, beta-secretase and presenilin-1, are found together with APP inside the packet. Beta-secretase and presenilin-1 are thought to be the main enzymes that process APP and create amyloid-beta peptide. Finding them together inside the cell suggests that APP processing may be part of a normal cell transport function that is somehow disrupted in Alzheimers disease, according to Goldstein.
The scientists compared cell transport in neurons of normal mice and mutant mice in which the APP protein is missing. In nerve cells of the mutant mice, they found that APP, beta-secretase and other cellular cargo, in addition to the motor protein kinesin, stay mainly in the cell body, suggesting that when APP is missing, normal cell cargo transport is stalled.
The scientists also found that amyloid-beta and another portion of APP, called the C- terminus, are made in these compartments inside living cells and inside compartments isolated from nerve cells. The C-terminus is the portion of APP where the motor molecule kinesin attaches. Goldstein and his colleagues found that when enzymes break off the C-terminus, kinesin is liberated and the transport process is disrupted. These results also represe
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
5-Dec-2001