For the first time, and to the astonishment of many of
their colleagues, researchers created what they call Alzheimer’s in a Dish — a
petri dish with human brain cells that develop the telltale structures of
Alzheimer’s disease. In doing so, they resolved a longstanding problem of how
to study Alzheimer’s and search for drugs to treat it; the best they had until
now were mice that developed an imperfect form of the disease.
The key to their success, said the lead researcher,
Rudolph E. Tanzi of Massachusetts General Hospital in Boston, was a suggestion
by his colleague Doo Yeon Kim to grow human brain cells in a gel, where they
formed networks as in an actual brain. They gave the neurons genes for
Alzheimer’s disease. Within weeks they saw the hard Brillo-like clumps known as
plaques and then the twisted spaghetti-like coils known as tangles — the
defining features of Alzheimer’s disease.
The work, which also offers strong support for an old
idea about how the disease progresses, was published in Nature on Sunday.
Leading researchers said it should have a big effect.
Images of the clumps known as plaques, seen in orange,
disrupting a network of human nerve cells, in green, within a petri dish
containing cells mimicking the brain of an Alzheimer's patient. CreditDr. Doo
Yeon Kim and Dr. Rudolph Tanzi, Massachusets General Hospital “It is a giant
step forward for the field,” said Dr. P. Murali Doraiswamy, an Alzheimer’s
researcher at Duke University. “It could dramatically accelerate testing of new
drug candidates.”
Of course, a petri dish is not a brain, and the petri
dish system lacks certain crucial components, like immune system cells, that
appear to contribute to the devastation once Alzheimer’s gets started. But it
allows researchers to quickly, cheaply and easily test drugs that might stop
the process in the first place. The crucial step, of course, will be to see if
drugs that work in this system stop Alzheimer’s in patients.
The discovery, said Dr. Sam Gandy of the Icahn School of
Medicine at Mount Sinai in New York, is “a real game changer” and “a paradigm
shifter.” He added, “I’m really enthusiastic to take a crack at this in my
lab.”
Dr. Tanzi is now starting an ambitious project to test
1,200 drugs on the market and 5,000 experimental ones that have finished the
first phase of clinical testing — a project that is impossible with mice, for
which each drug test takes a year. With their petri dish system, Dr. Tanzi
said, “we can test hundreds of thousands of drugs in a matter of months.”
He already has used his system to look at drugs designed
to prevent the formation of amyloid, the protein that clumps into plaques. The
drugs, he reports, prevented both plaques and tangles in the petri dishes. Some
are in clinical trials, and it is not known if they work in people. One was
tested in patients and failed because it was too toxic. One hope is to find
drugs for other diseases that are known to be safe and work on Alzheimer’s in
the petri dish.
Continue reading the main storyContinue reading the main
storyContinue reading the main story He also found an enzyme needed to make
tangles after plaques are present. When he blocked that enzyme, plaques formed
but not tangles. The enzyme is another potential drug target, he said.
Dr. Gandy wants to use the system to study the effects of
genes that predispose someone to have Alzheimer’s, especially the most powerful
one, ApoE4, which contributes to about half of all Alzheimer’s cases. No one
really knows how or why it is linked to the disease, Dr. Gandy said.
“I think I would go after that to begin with,” he said.
Dr. Tanzi said that once his group had gotten the idea of
growing neurons in a gel, setting up Alzheimer’s in a dish system had been
straightforward. Group members used human embryonic stem cells — those cells
that can become any cell of the body — and grew them with a mixture of
chemicals that made them turn into neurons. They gave those neurons Alzheimer’s
genes and grew them in wells in petri dishes that were lined with a
commercially available gel. Then they waited.
“Sure enough, we saw plaques, real plaques,” Dr. Tanzi
said. “We waited, and then we saw tangles, actual tangles. It looks like you
are looking at an Alzheimer brain.”
All that was required to start the process was the
Alzheimer’s gene, which made cells produce an excessive amount of a normal
protein, beta amyloid. Previously, researchers had tried to grow the disease in
a dish of liquid, but the neurons did not connect or develop plaques and
tangles.
The controversy over how and why Alzheimer’s gets going
dates back three decades, when Dr. George G. Glenner, who died in 1995,
proposed a simple process. Beta amyloid starts to accumulate in the brain. It
turns into plaques. Neurons respond by making tangles. The combination proves
fatal for brain cells, and dementia sets in.
“He said, ‘This is how the disease starts,’ ” Dr. Tanzi
said. “But for 30 years there was no proof that amyloid drives the rest of the
disease.”
In fact, when researchers put human Alzheimer’s genes in
mice, the animals made excess beta amyloid and developed plaques but never had
tangles. It was not clear why. Was excess amyloid only part of what was needed?
Or were mice just too different from humans? Lacking anything better, mice were
used anyway to test experimental drugs. But more than 20 drugs that seemed as
if they would cure Alzheimer’s, based on studies in mice, utterly failed when
tested in patients.
“The lack of a viable model for Alzheimer’s has been the
Achilles’ heel of the field,” Dr. Doraiswamy of Duke said.
Some said that the amyloid hypothesis was correct and
that the drugs failed because they were not potent enough or were given too
late, when the disease was well established. But others asked if amyloid was
the right target. Many proposed going after another protein instead, tau, a
normal constituent of neurons that becomes deformed into tangles when a person
has Alzheimer’s disease.
Even those who insisted on the amyloid hypothesis often
elaborated on it, saying that first amyloid accumulates and then a litany of
other things go wrong — cell damage and inflammation and molecular stress —
that finally lead to tau and tangles. “There was a big black box of things
going wrong,” Dr. Tanzi said.
But, he said, the more complex model was refuted by his
study. Tangles formed with nothing but the presence of amyloid plaques.
And drugs that block beta amyloid prevent both plaques
and tangles from forming, Dr. Tanzi and his colleagues reported.
“This provides strong support to the amyloid hypothesis
and essentially cinches the serial link between amyloid and intracellular
tangles,” Dr. Doraiswamy said. Now, he added, the challenge is to show that
drugs that work in this system also help patients.
Dr. Frank Talamantes, Ph.D,
Professor of Endocrinology (Emeritus)University of California
Santa Cruz, California, 95064
Residence: 83 Sierra Crest Dr.
El Paso, Texas 79902
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