December 06, 2001
Defective Cell Transport Suggested in Alzheimer's Disease
Over the last few years, scientists have been successful in
identifying genes implicated in Alzheimer’s disease, but they are
just beginning to piece together what the Alzheimer's-disease-related
proteins do in the cell, and how they may cause disease.
Now, Howard Hughes Medical Institute investigator Lawrence
Goldstein and his colleagues at the University of California, San
Diego, report in the December 6, 2001, issue of the journal
Nature that several of these proteins are involved in
trafficking cargo inside nerve cells. In a related report published in
the November 8, 2001, issue of the journal Neuron, a team of
researchers led by Goldstein showed that disruption of the transport
system caused by defects in these proteins can lead to nerve cell
death.
“If you look at the history of breakthroughs in disease, often the understanding of what proteins normally do gives important clues to what is aberrant in disease.”
Lawrence S. B. Goldstein
“If you look at the history of breakthroughs in disease, often
the understanding of what proteins normally do gives important clues to
what is aberrant in disease,” said Goldstein. “This has
been much less useful so far in understanding neurodegenerative
diseases. Neurologists see protein aggregations in diseased brains, but
there is a big gulf in understanding whether the generation of protein
aggregates causes the disease per se.”
In the brains of patients with Alzheimer’s disease, a peptide
called amyloid-beta accumulates in areas of the brain where nerve cells
die en masse, leading to progressive dementia. Goldstein and his
colleagues studied the role of amyloid precursor protein (APP), which
gives rise to the abnormal amyloid clumps.
Using mouse neurons as a model, the scientists showed that APP
serves as an attachment point for a molecular motor called kinesin,
which transports packets of protein from the main cell body along the
length of the cell. This cell transport mechanism is crucial to nerve
cells, which have the unique property of sending out tendrils, called
axons, up to several feet from the main cell body to innervate distant
parts of the body. Communication in these cells is long distance,
explained Goldstein.
“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
Alzheimer’s-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 Alzheimer’s
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 represent one of the first detailed
studies of amyloid-beta being formed in compartments inside living
nerve cells.
To complement the mouse studies, the researchers studied the effects
of various APP gene mutations in fruit flies. As reported in the
Neuron article, Goldstein’s team showed that excess APP
containing amyloid-beta region and the C-terminus caused neural cell
death, but amyloid-beta containing APP alone did not. These results and
research by other investigators led Goldstein's team to conclude that
the C-terminus may carry a cell death signal that can be initiated when
transport fails.
“Our results suggest maybe it is the cleavage to liberate this
C-terminal piece that is sending a signal back to the cell body to
die,” said Goldstein. “It certainly is an interesting clue
and makes sense in the context that if a cell is damaged it needs to be
able to signal to the nucleus.”
The results also are consistent with the epidemiological observation
that people who suffer trauma to the brain are more susceptible to
developing Alzheimer’s disease, Goldstein added. The
investigators are now trying to isolate the death signal for further
study.
While Goldstein says the results are not definitive, he suggests
studies such as these should help sort out the question of which
protein products lead down the path to cell death seen in
Alzheimer’s disease.
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