[Homestead] Alzheimer progress blocked with transthyretin protein

Tvoivozhd tvoivozd at infionline.net
Tue Sep 14 12:10:24 EDT 2004

tvoivozhd---possible progress in one of the most terrible diseases known 
to man.

/Source:/ 	*University Of Wisconsin-Madison* 	
/Date:/ 	2004-09-13
/URL:/ 	http://www.sciencedaily.com/releases/2004/09/040913085410.htm


    Discovery May Halt Progression Of Alzheimer's

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 

"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

*Editor's Note:* The original news release can be found here 


/This story has been adapted from a news release issued by University Of 

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