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Neuron "Traffic Jam" Marks Early Alzheimer’s Disease
Feb. 26, 2005 - Early Alzheimer's disease may be
precipitated by a “traffic jam” within neurons that causes swelling and
prevents proper transport of proteins and structures in the cells,
according to new studies by Howard Hughes Medical Institute researchers.
In mouse models of Alzheimer's disease and in human
brain samples from people with the disease, researchers observed a
characteristic breakdown in neurons that appears to prevent the normal
movement of critical proteins to the communications centers of the nerve
cells. In a vicious cycle, the traffic jam also could increase
production of an abnormal protein that clogs neurons, leading to their
failure and eventual death.
The researchers said their findings could provide information that might
be used to develop drugs to preserve the molecular transport system and
thus the viability of brain cells otherwise lost in Alzheimer's. The
findings also could ultimately lead to distinctive markers of early
Alzheimer's disease that could be used in early diagnostic tests for the
disorder, they said.
The research team led by Lawrence S. B. Goldstein,
a Howard Hughes Medical Institute investigator at the University of
California, San Diego (UCSD), reported their findings in the February
25, 2005, issue of the journal Science. Goldstein and his
colleagues at UCSD collaborated on the studies with a researcher at the
Albert Einstein College of Medicine.
According to Goldstein, there has been evidence
that late-stage Alzheimer's disease involves a failure of the machinery
that transports proteins within neurons. In studies with fruit flies,
Goldstein and others had observed that overexpression of the gene for a
key protein that underlies Alzheimer's pathology, called beta amyloid
precursor protein (beta-APP), triggers defects in axonal transport. A
defective version of beta-APP is cleaved to form an aberrant form of
amyloid beta (A-beta) peptide that makes up the plaques that surround
the neurons of people with Alzheimer's disease.
“With the findings from fruit flies as our guide, we decided to look at
mouse models of Alzheimer's disease early in their life, before plaque
formation, to see if we could detect early evidence of abnormal axonal
transport,” said Goldstein. The researchers used mice that had been
engineered to have an abnormal production of human A-beta peptide that
produced Alzheimer's-like plaques and subsequent neural degeneration.
The scientists' analyses of the neurons in those
mice revealed clear defects, said Goldstein. “What we saw quite early in
the life of those animals — well before any plaque deposition — were
obvious axonal defects,” said Goldstein. “We saw large swellings in
their axons. And when we looked at those swellings using electron
microscopy and biochemical markers, they looked just like the axonal
transport blockages we saw in fruit flies.” Detailed studies of the
neurons revealed what Goldstein termed a “traffic jam” of
transport-related proteins, organelles and sac-like vesicles that are
the cargo-carriers for cellular proteins.
Goldstein and his colleagues also examined brain
sections taken at autopsy from humans with different stages of
Alzheimer's disease. They detected the same kinds of swelling in those
samples that they had seen in the mice. “This was a small, initial
neuropathological study, but we believe that it is significant,” said
Goldstein. “We found in the early cases a very strong, statistically
meaningful swelling in the neurons.”
The researchers tested whether they could enhance
the pathology they observed in the mice and humans by reducing the
levels of a key transport protein, kinesin-1, the cell's principal
molecular motor for transporting proteins. “We made a modest reduction
in the level of a motor protein called kinesin-1 in the mice, and we got
a considerable increase in plaque production and plaque deposition,”
said Goldstein. “This makes it clear there is some mechanistic
connection between the transport deficit and plaque deposition.
“So, our hypothesis is that in familial Alzheimer's
disease — or in disorders such as Down syndrome where beta-APP is
overexpressed — those defects cause early failure in cellular
transport,” he said. “And those failures then stimulate further
production of A-beta peptide, which may further poison the machinery.”
Goldstein theorized that Alzheimer's disease might
develop spontaneously in people without an overt genetic defect, as the
transport machinery in their neurons breaks down with age. “A person
could have a predisposition to the disease, or it could just be that as
time progresses, one person could by chance accumulate these blockages
more than another,” said Goldstein. “And randomly, some people would
accumulate more than others, enough to cross a critical threshold and
tip the scale toward disease.”
Goldstein emphasized that any application of these
findings to potential diagnostic tests or new therapies remains
speculative at this time. “However, if tracers could be developed that
would reflect transport function, there could be imaging methods that
might be helpful for diagnosis,” he said. “And, if these findings
continue to hold for humans, the transport machinery could be a target
for drugs to preserve that machinery.”
The researchers plan to continue their exploration
of the transport machinery's involvement in Alzheimer's pathology by
using human embryonic stem cells to differentiate into neurons in
culture. Their goal is to alter those neurons genetically by introducing
mutations know to cause Alzheimer's disease in people, to then test for
transport defects, and then study whether those defects produce
pathology similar to that seen in Alzheimer's. One of the questions they
will also ask is whether amyloid plaques poison the transport machinery.
If the experiments do, indeed, confirm the predictions of the transport
hypothesis, then neuronal cultures could prove valuable in testing
diagnostic and therapeutic approaches, said Goldstein.
The researchers are also analyzing more brain
tissue samples from humans with Alzheimer's disease, to confirm their
findings of the early transport defects and their effects on neuronal
death.
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