Alzheimer Researchers See Protein as Target for Drugs

A protein discovered less than a decade ago appears to play a role in whether symptoms of Alzheimer’s disease emerge, suggesting another avenue for exploration in efforts to find a treatment.

An abnormal form of the novel protein dubbed TDP-43 was tied to smaller brain volume and almost guaranteed that people with it would suffer memory loss, according to findings presented today at the Alzheimer’s Association International Conference in Copenhagen. Almost one in five of those without it had no symptoms, despite deposits in their brains of the amyloid plaque that defines Alzheimer’s.

Researchers have focused on two proteins, beta amyloid and tau, in a century-long quest to understand Alzheimer’s. While basic research is still being conducted to uncover why those two proteins congregate in the brains of patients, there has been little progress in finding medicines to control them and slow or prevent the most common form of dementia in the elderly.

“This injects new vigor in the fight against Alzheimer’s disease,” said Keith Josephs, the lead author and a neurologist at the Mayo Clinic in Rochester, Minnesota, in a telephone interview. “The world has focused on two proteins, beta amyloid and tau. TDP-43 is going to be the new kid on the block.”

Biogen Idec Inc. is conducting preclinical tests to understand TDP-43 and its potential as a target for neurodegenerative diseases, Shannon Altimari, a spokeswoman for the Cambridge, Massachusetts-based company, said in an e-mailed statement. Ben Wolozin of Boston University’s Alzheimer’s Disease Center, is starting a company called Aquinnah Pharmaceuticals to develop compounds targeting the protein.

‘Major Player’

Developing potential drugs to target the protein would take years, and the pharmaceutical industry’s track record so far gives little cause for optimism. Still, having a goal to shoot at is encouraging, Wolozin said in a phone interview.

“This is beginning to present the case that actually TDP-43 is a major player in the cognitive loss associated with Alzheimer’s disease,” he said.

Researchers are still trying to tease out details about how TDP-43 works. It’s found in the nucleus of the cell and transcribes DNA, the first step in gene expression. It’s active during the production and programming of other proteins that have specific roles in the cell, thereby helping determine how the body will function.

In its abnormal form, the protein is found floating in the cytoplasm, the fluid outside of the nucleus. There are several differences between the normal and abnormal forms of TDP-43, including its weight, Josephs said. It’s possible the abnormal form migrates out of the nucleus and can’t get back in, he said.

Memory Structure

If it’s not in the nucleus, it can’t be doing its job, Josephs said in a telephone interview.

The researchers examined 342 people who had donated their brains to science for the presence of an abnormal form of TDP-43, finding it in 57 percent of the group. They also examined the volume of the hippocampus, the main memory structure in the brain that’s damaged and shrinks in Alzheimer’s patients.

“The brains of the ones that had the abnormal protein had more severe memory loss than those who did not, they had more severe shrinkage in the hippocampus and most importantly, of those with the protein, 98 percent were cognitively affected before they died,” Josephs said.

Among the elderly patients who didn’t have an abundance of the abnormal protein, just 81 percent were suffering memory loss, even if they had amyloid buildup in their brains, he said.

‘Blown Away’

“Almost 20 percent of those without the abnormal protein were normal when they died,” he said. “That surprised me. We were all blown away. Even though you have Alzheimer’s disease, the plaques and the tangles, you are still 10 times more likely to be normal if the abnormal form is absent.”

Studying TDP-43 will be more difficult than work on amyloid, which has been largely focused on trying to prevent it from accumulating and removing it once it has settled into the brain. The new protein is essential for the normal function of cells, and it’s likely that it becomes damaged at some point after previously working fine. Finding the trigger may be key.

“Cells depend on the protein,” Josephs said. “We’re going to have to prevent it from becoming bad.”

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