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Salk Researchers Halt The Progression Of Alzheimer’s In Very Old Mice

Researchers at the Salk Institute are making progress on a compound that they believe could potentially stop Alzheimer's disease in its tracks. To show just how promising their drug candidate is, they put it through unusually hard experiments.

Researchers at the Salk Institute are making progress on a compound that they believe could potentially stop the progression of Alzheimer's disease. No drug currently on the market can do that, so it's a bold claim. But by putting their compound through an especially rigorous experiment on lab mice, they've shown just how promising it is.

Marguerite Prior, the lead scientist behind J147, says the Alzheimer's drug candidate is ready for human clinical trials.

Marguerite Prior and her colleagues first published research on a compound called J147 in late 2011. The substance is derived from curcumin, found in the colorful Indian spice turmeric. They showed that J147 can improve multiple types of memory in mice with the disease. More significantly, they demonstrated that it could prevent synapses in the brain from disconnecting, effectively halting the disease.

The scientists are back with a follow-up study this week. This time, they made things even harder for themselves.

Prior says that before administering J147, "We aged the Alzheimer's mice to 20 months old, which is very old for an Alzheimer's mouse." The experimental design, outlined in a paper published today in Alzheimer's Research & Therapy, separates this research from most of the work being done on Alzheimer's.

You might think that scientists would always use age-appropriate mice when studying an age-related disease like Alzheimer's. But you'd be wrong. Researchers typically experiment on young mice genetically engineered to acquire Alzheimer's later in life. That's not such a great model of how Alzhiemer's plays out in the real world. Unlike lab mice, people don't get Alzheimer's treatment before their symptoms show up.

That's why Prior waited for her mice to get old and exhibit memory problems before putting J147 in their food. Even at this advanced stage in the disease, the mice improved significantly. Prior says, "We found that J147 was able to reverse, even at that late stage in the disease, memory deficits."

David Schubert is the head of Salk's Cellular Neurobiology Laboratory, which has been working on a novel Alzheimer's drug candidate for years.

Prior's age-based methodology fits in well with David Schubert's lab at Salk. Schubert thinks that pharmaceutical companies have become too fixated on amyloid plaques when trying to discover new Alzheimer's drugs. It's no wonder that their drugs fail so often, according to Schubert. Just last week the results from a major study on Baxter International's Alzheimer's drug candidate Gammagard came back. It fared no better than a placebo.

Schubert's lab looks at Alzheimer's differently. ""We thought that another way to approach drug discovery was based on age, old age, rather than this amyloid pathway," says Schubert. "Alzheimer's should be looked at not as one causative agent, but as a whole cumulative spectrum of age-associated things that going wrong in the brain."

Prior and her co-authors didn't just look at how J147 affected progression of the disease. In a second experiment, they tested J147's memory-boosting properties against the most commonly prescribed Alzheimer's drug, Aricept. Like all Alzheimer's medications currently approved by the FDA, Aricept only adresses symptoms, not the disease itself. And it loses its effectiveness over time.

The Salk researchers staged the head-to-head comparison by putting mice through a water maze that tests spatial memory. Water-phobic mice will do their best to get to an elevated platform in the middle of this pool, and you can train them to remember where the platform is. But the mice in this experiment had been doped with scopolamine, a drug that impairs memory.

When the researchers removed the platform, they saw the J147-treated mice swim their way right to where the platform used to be. They remembered where it was, showing marked improvements in spatial memory compared to the mice who received only Aricept. These outcomes suggest that J-147 improves short-term and spatial memory, while Aricept only helps with the former.

Schubert says this research brings cause for optimism, but cautions that taking the next step will be a challenge. His lab is ready to submit an investigational new drug application with the FDA. But that process will cost $1.5 million, no small sum for a lab using unconventional methods in a post-sequestration funding landscape.

Prior hopes to begin human clinical trials soon. "We're ready," she says. "We're just trying to get the money together."


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