Link found between Alzheimer's, mad cow protein

Thursday, February 26, 2009

2/26) 19:56 PST -- The latest in a recent flurry of clues on the workings of Alzheimer's disease comes from Yale University researchers who found a link between the disorder and the prion protein, which can cause mad cow disease and other maladies.

The Yale team found that the prion protein, whose normal function is to maintain brain health, may contribute to nerve damage if it becomes entangled with a protein fragment that scientists consider a chief suspect as a cause for Alzheimer's disease.

That suspect fragment, the amyloid beta peptide, builds up in the gluey plaques in the brain that are a characteristic sign of Alzheimer's, a progressive neurodegenerative disease. The amyloid peptide seems to stick to the prion protein, block its benign effects and interfere with learning and memory, the Yale group said in a paper published Wednesday in the journal Nature.

'Very tantalizing'
"It's very tantalizing," said Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease, who wrote a commentary on the Yale theory in the same issue. Mucke is part of a robust community of Bay Area scientists who are trying to ferret out the root causes of Alzheimer's disease and develop new medicines.

The prion work adds to a spate of new leads produced at the Gladstone Institute at UCSF's Mission Bay campus, the Buck Institute for Age Research in Novato, South San Francisco biotechnology leader Genentech Inc. and other research teams.

The study by Dr. Stephen Strittmatter and his Yale colleagues raises the possibility of a link between Alzheimer's and the family of prion diseases that includes mad cow disease and a related human neurodegenerative illness called Creutzfeldt-Jakob disease. But the evidence so far shows no sign that Alzheimer's disease involves a prion protein with the deformed structure seen in mad cow and Creutzfeldt-Jakob disease. Such misfolded prions can arise from genetic mutations or can be carried into the body by infectious particles from tainted meat.

Mucke said that the prion protein, if it is involved in Alzheimer's, is probably in its normal form. There's no evidence that the disease somehow releases infectious prions. "I don't believe it's communicable," he said.

Other new theories
The prion study does not contradict other new theories about Alzheimer's, which all suggest fresh potential mechanisms by which the amyloid peptide or its parent, a protein called APP, may wreak destruction on the brain, said Dr. Dale Bredesen of the Buck Institute. Each theory opens potential new avenues to experimental therapies, he said. So far, much of the drug discovery in Alzheimer's has been focused on simply clearing the amyloid peptide and its plaques from the brain, on the theory that they cause broad physical or chemical damage, Bredesen said. But new work shows that APP and the amyloid peptide are involved in sensitive signaling networks that can go awry and destroy healthy nerves.

"I think we're seeing a fundamental switch in the view of the disease," he said. Recent failures of experimental drugs aimed at the amyloid peptide alone suggest that additional tactics are needed, he said. "Amyloid beta was the tip of the iceberg, but there's more."

Bredesen has his own overarching theory. He sees APP as a molecular switch on the nerves that flips between health and destruction. The protein can split up into three parts that each nourish the nerve. Or it can fracture differently into four parts that each attack the nerve - and one of those destructive four is the amyloid peptide, he said.

Search for a therapy
In the search for a possible therapy for Alzheimer's, Bredesen is focusing on a molecule that seems to block the destruction switch. The nerve growth factor netrin-1 appears to curb the release of the amyloid peptide from APP, he said. Work is under way on methods to deliver netrin-1 to people with early signs of Alzheimer's, but it could take five years to produce an approved drug, he said.

Mucke said the Gladstone Institute is working on an array of strategies, which include preventing the amyloid peptide from finding molecules that pass along its destructive signals.

Scientists are starting to see Alzheimer's as a complex disease like cancer or hypertension, which can arise from various root causes. That means patients may need a cocktail of several drugs, and maybe a custom-made mix for each individual.

"I'm absolutely convinced that different people get Alzheimer's for different reasons, and drug development will have to take that into account," Mucke said.

E-mail Bernadette Tansey at btansey@sfchronicle.com.

This article appeared on page A - 8 of the San Francisco Chronicle


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