X-Message-Number: 24652
Date: Fri, 17 Sep 2004 20:18:50 -0700 (PDT)
From: Doug Skrecky <>
Subject: Discovery may halt progression of Alzheimer's

(It is amazing that this message was out-dated by the time it hit the net.
The phrase "may halt" now needs to be replaced by "has halted".)

---------- Forwarded message ----------
In a finding that may cause a dramatic shift in the way scientists and
researchers search for a therapy for Alzheimer's disease, a team of
researchers led by Jeff Johnson, an associate professor at the School of
Pharmacy, has discovered that increased expression of a protein called
transthyretin in the brain appears to halt the progression of the
disease. The findings appear in the current issue of The Journal of
Neuroscience.

"This work shows convincingly that if we can intervene in Alzheimer's
pathology by introducing molecules and drugs into the brain and increase
transthyretin levels, we could slow the progression of the pathology,"
says Johnson, who co-authored the report with Thor Stein, a former
graduate student in UW's M.D./Ph.D. program who performed most of the
experiments. "Even if patients have plaque formation in the brain, they
still could have normal function."

For years, researchers have focused on creating an animal model that
mimics the pathology of Alzheimer's disease to test potential therapies.
By genetically engineering mice to express mutated genes from the
families of patients with early-onset Alzheimer's disease, researchers
produced several mouse lines that over-express the human amyloid
precursor protein (APP), a protein involved in the disease development.
While the mice developed plaque formation in their brains, they didn't
develop the other hallmark of Alzheimer's disease -- neurofibrillary
tangles, a leading indication that neural cells are dead or dying.

Most researchers noticed this and continued to search for a way to
create the perfect mouse model. Johnson had a different thought.

"I said to myself, everybody is trying to kill neurons in mice to create
the Alzheimer's pathology," he explains. "And here we have a mouse that
has amyloid deposition and plaques yet no neurons are dying. Let's try
to figure out why these mice aren't getting the disease."

The answer was surprising, and could completely alter the way
researchers think about treating Alzheimer's disease.

Johnson's research is based on the widely held amyloid hypothesis: When
amyloid precursor protein (APP) is cut into pieces in the human brain,
there are "good" cuts - proteins that help to protect neurons - and
"bad" cuts, toxic beta-amyloid protein that, when present in large
amounts, causes massive neural cell death, leading to cognitive function
loss. In Alzheimer's patients, "bad-cut" proteins significantly
outnumber "good cut" proteins.

Stein, under Johnson's supervision, analyzed the brains of the mice with
plaque formation, and noticed something interesting: The levels of a
pair of specific proteins, transthyretin and IGF-2, increased
dramatically. Since transthyretin had been shown in test tubes to bind
to the toxic beta-amyloid protein, Johnson and Stein hypothesized that
in the mice, the transthyretin was preventing the "bad cut" toxic
beta-amlyoid protein from interacting with the neuronal cells, thereby
preventing tangle formation and subsequent neuronal cell death.

"Somehow, the adapted mechanism in the mice was due to the balance
between the good cut and the bad cut," says Johnson. "The good cut
product was causing the increase in transthyretin, which was balancing
the toxicity of the beta-amyloid, or bad-cut protein."

Further experimentation bore out their theory. When Stein introduced an
antibody into the mouse brain that prevented transthyretin from binding
with beta-amyloid protein, the mice developed early signs of
neurofibrillary tangles and increased neuronal cell death. Johnson and
Stein verified that this "good" cut product has similar protective
effects in human brain tissue in vitro. The latter finding is
particularly significant.

"If we couldn't show that, we wouldn't have known if this protective
mechanism is as relevant to humans as it was to mice," Johnson explains.

The next question - and it's a big one - involves developing a reliable
method to deliver transthyretin into the brain, or developing drugs that
increase transthyretin expression in the brain to combat the
neurotoxicity of beta-amyloid.

"This gives us a great opportunity to identify a new concept in the
field that other people and drug companies will pick up on," says
Johnson. "Hopefully this will spur a new approach to Alzheimer's
disease. Instead of treating the cognitive symptoms, we can actually
prevent the loss of the neurons that result in the cognitive symptoms."

Johnson foresees a time when family members with a genetic
predisposition to Alzheimer's disease could take a yet-undeveloped drug
or molecule to increase transthyretin protein and prevent the disease
from developing. It could also theoretically halt the progression of the
disease in patients in the early stages of the pathology, preserving a
higher level of cognitive function.

The Wisconsin Alumni Research Foundation (WARF) has filed a U.S. patent
application on behalf of the chool of Pharmacy on specific protein
sequences that confer this protective effect. In the coming months, WARF
hopes to begin licensing this technology to drug companies that can
begin researching an effective delivery method.

Johnson and Stein believe that these new discoveries may eventually be
combined with other therapies to help prevent the progression of
Alzheimer's disease.

"What makes this interesting and novel is that nobody has really
identified this mechanism for potential therapeutics," Johnson says. "I
believe there will be drugs that cross the blood-brain barrier that can
be used for Alzheimer's therapy. We'll find those molecules. They may
already be out there, but nobody has looked at them in this context."

Johnson and Stein's research was and continues to be funded by the
National Institute of Environmental Health Sciences. To view the report
in full, visit http://www.jneurosci.org

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