February 25, 2005
Neuronal "Traffic Jam" Marks Early Alzheimer’s Disease
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.
“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.”
Lawrence S. B. Goldstein
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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