Developing Compounds to Enhance Cognitive Function

Mauro Costa-Mattioli (320x240)
Dr. Mauro Costa-Mattioli, Department of Neuroscience

Memory is essential for human experience, and most of what we know about the world is stored as memory. There are two memory systems: short-term memory (STM), which lasts minutes, and long-term memory (LTM), which lasts for years or even a lifetime. Memories are stored in the brain as changes in the strength of the connections between neurons, and cognitive functions arise from the finely-tuned coordinated interactions of a large number of neurons widely distributed throughout the brain.

Since memory is at the center of our identity, the loss of memory leads to the loss of self. Learning and memory disorders strike the brain not only during development—for example, in Autism and Down syndrome—but also in the adult— for instance in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and aging. By 2030, the incidence of Alzheimer’s disease is expected to be 15 million in the U.S. Currently, there are no treatments that can prevent, delay or reverse the memory problems associated with Alzheimer’s or other cognitive disorders including Autism, Parkinson’s disease, Down Syndrome, PTSD, and addiction.

The lab of Dr. Mauro Costa-Mattioli, assistant professor of Neuroscience, has provided novel genetic, physiological, pharmacological, behavioral, and molecular evidence that the double-stranded RNA-activated protein kinase (PKR) negatively regulates memory storage. They have shown that genetic inhibition or pharmacological inhibition of PKR enhances learning and long-term memory formation in mice. Likewise, they have developed a class of novel small molecule inhibitors, which block PKR (PKRi), and have shown that they enhance long-term memory storage. This evidence suggests that cognition may be enhanced in an individual by providing a therapeutically effective amount of the PKRi. Since the activity of PKR is altered in several neurological disorders, including Alzheimer’s Disease, Parkinson’s, and Huntington’s disease, this kinase and inhibitor present a promising new treatment for cognitive dysfunction. His lab is the only lab in the world to provide two mouse models of enhanced cognition as well as a memory-enhancing drug.

Applications/Advantages

• Development of a novel, small molecule inhibitor of PKR, and demonstration that it enhances long-term memory formation.

• Their studies address an important unmet medical need - Cognitive disorders (from Aging to Alzheimer’s disease to PTSD).

• The Costa-Mattioli lab has already provided two mouse models of enhanced cognition and also molecules (drugs) that can enhance memory formation.

• The inventors use a multidisciplinary approach that combines mouse and fly genetics, molecular biology, chemical biology, behavior, electrophysiology(at the single cell, synaptic and network level) imaging and drug discovery which will provide useful leads to treat cognitive dysfunction.

BLG Project Manager

Lisa Beveridge (lisa.beveridge@bcm.edu)