Compound Restores Memory Function in Mouse Alzheimer’s Model

This research was supported by BrightFocus

Researchers from Yale School of Medicine have discovered a promising new drug compound that reverses some Alzheimer’s effects on memory in mice.

The work directly stems from a 2008-11 BrightFocus grant to Paul Lombroso, MD, who’s on the Yale neurobiology and psychiatry faculty and directs its Laboratory of Molecular Neurobiology. He is senior author of a report published in PLoS Biology August 5.

They found that a protein drug compound, known as TC-2153, blocks the Alzheimer’s disease linked effects of another protein called striatal-enriched tyrosine phosphatase (STEP). At high levels, STEP prevents synaptic strengthening in the brain—something vital to memory function.

It’s actually one of several breakthroughs tied to this BrightFocus grant, which included 2000 Nobel Laureate Paul Greengard, PhD, of Rockefeller University, as coinvestigator. Four years ago, these researchers established the connection between increased STEP levels and Alzheimer’s changes in mice, and showed that removing STEP in a knockout model had the effect of restoring synaptic connections—reported in the Proceedings of the National Academy of Sciences on October 18, 2010.  

Since their discovery of STEP, Lombroso and his team have been searching for a drug that would block its damaging effects on brain synapses. It was already known that STEP levels increase in Alzheimer’s disease due to beta amyloid buildup. As beta amyloid accumulates in the cells, it inhibits the cellular functions that would destroy excess levels of STEP. To make matters worse, STEP is also implicated in allowing beta amyloid’s entry into neurons. While this study has particular relevance to Alzheimer’s disease, STEP is tied to other neurological disorders as well, including schizophrenia, Parkinson's disease, and fragile X syndrome.

With much of the pharmaceutical efforts concentrated directly on beta amyloid, Lombroso and colleagues focused on finding a STEP inhibitor, studying thousands of small molecules in their quest.  During their search, they learned more about how STEP interacts with Alzheimer’s disease, and entered into a research collaboration with the pharmaceutical company, GlaxoSmithKline, as described in a BrightFocus News Update earlier this year.

The latest accomplishment was to show their lead molecule, TC-2153, binds tightly to STEP molecules and thus, even in the presence of high STEP levels, blocks the protein’s destructive effect on neural synapses. Treating mice with a single dose of TC-2153 improved their cognitive function.

“It’s a promising chapter in a long and dedicated research effort,” says BrightFocus Foundation Vice President of Scientific Affairs Guy Eakin, PhD. “Mice have been revolutionary for the understanding of Alzheimer’s disease. And now, Dr. Lombroso’s current efforts to expand his studies to primates and other animals will be a crucial next step in testing the appropriateness of this drug for humans.”

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