Hi everyone!

Here's a fascinating new approach to treating AD.

/Darryl lurking mode back on
(I'm hiding at home writing my thesis).

http://www.news.wisc.edu/10088.html

(Posted: 9/2/2004)

Aaron Conklin

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."