Research

Dave R. Schubert, professor and head of the Cellular Neurobiology Laboratory, studies hormones and other substances that affect the activities and survival of brain cells. Much of his research is providing new insights into Alzheimer's disease and other degenerative brain disorders.

Schubert has been studying beta amyloid protein, a substance that accumulates in the brains of Alzheimer's patients. Schubert has shown that this protein can cause nerve cell death, while vitamin E can protect cells from its toxic effects.

A recent study conducted by scientists at UCSD showed that Vitamin E does, in fact, slow the progression of Alzheimer's. Schubert's lab also is studying the mechanisms of cell death in Parkinson's disease, stroke and ischemia, with the goal of trying to identify drugs that inhibit these processes.

"Our research group is using a novel drug discovery paradigm developed in our laboratories to make drugs for Alzheimer's and Parkinson's diseases, stroke and diabetic complications. The goal is to get these new drugs through the initial stages of development and into the clinic as rapidly as possible."

There are currently no effective treatments for any age-associated neurological disease, including Alzheimer's, Parkinson's or the neurological complications of diabetes. There are many reasons for this deficiency. One is the innate disease complexity, for in most cases the nerve cells die from multiple stresses and toxins. Therefore, drugs to treat these conditions must block the different pathways that together kill cells, not just a single target.

Plants synthesize drug-like molecules to defend themselves against pathogens and predators. Most of these molecules have numerous biological activities, but they have not yet been exploited for the treatment of neurodegenerative diseases. Scientists in the Schubert laboratory are using a series of innovative biological assays to identify plant products that are broadly neuroprotective. They then use medicinal chemistry to improve their drug-like properties. To date, they have identified two lead compounds that meet the above criteria and have synthesized a series of much more potent derivatives that maintain the multiple biological activities of the parents.

The first is fisetin, which is found in strawberries and is orally active in animal models of Alzheimer's, Huntington's and Parkinson's. It is also very active in rodent models of stroke. Fisetin has a unique ability to protect from the vascular inflammation that is associated with all neurodegenerative conditions. Schubert's team also has made potent synthetic derivatives of curcumin, the major component of the Indian spice turmeric, that work extremely well in animal models of Alzheimer's and ischemic stroke. Some members of both groups of compounds are ready to start the FDA drug approval process, pending funding.

This work is being extended in three areas: refinement of the chemical structures to improve their pharmacological properties, characterization of the multiple molecular pathways that are responsible for the exceptionally neuroprotective properties, and testing in additional animal disease models. The ultimate goal is to get these compounds to the clinic to treat diseases for which there are currently no cures.

Left to right:
Chandramouli Chiruta, Antonio Jose Martins Currais, Pamela Maher, David Schubert, Marguerite Prior, Richard Dargusch, Jennifer Ehren

Salk News Releases

• Salk scientists develop drug that slows Alzheimer's in mice
  May 14, 2013
• Alzheimer's drug candidate may be first to prevent disease progression
  December 14, 2011
• Flavonoids could represent two-fisted assault on diabetic complications and nervous system disorders
  June 27, 2011
• Compound derived from curry spice is neuroprotective against stroke and traumatic brain injury
  December 14, 2010
• Natural compound shows promise against Huntington's disease
  November 15, 2010
• Stem Cells Yield New Clues to Glut of Glial Cells in Down's Syndrome, Glioblastoma, and Alzheimer's Disease
  March 13, 2009
• New pathway is a common thread in age-related neurodegenerative diseases
  January 29, 2009
• Salk study links diabetes and Alzheimer's disease
  May 15, 2008

Awards and Honors

• Jacob Javits Award, 1986
• Zenith Award, Alzheimer's Association
• Jacob Javits Award, 1993

Alzheimer's drug candidate may be first to prevent disease progression

December 14, 2011

A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease, based on the findings of a study published in PLoS ONE.

When given to mice with Alzheimer's, the drug, known as J147, improved memory and prevented brain damage caused by the disease. The new compound, developed by scientists at the Salk Institute for Biological Studies, could be tested for treatment of the disease in humans in the near future.