May 14, 2013

Salk Scientists Develop Drug that Slows Alzheimer's

The Salk Institute team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against pathologies associated with brain aging.

+Bob DeMarco
Alzheimer's Reading Room


Marguerite Prior holds a vial of J147

Scientists at the Salk Institute for Biological Studies say they may have found a drug that not only stops Alzheimer's disease, but might also reverse the symptoms of the disease.

The current research findings were published in the journal Alzheimer’s Research and Therapy.

"J147 is an exciting new compound because it really has strong potential to be an Alzheimer's disease therapeutic by slowing disease progression and reversing memory deficits following short-term treatment," says lead study author Marguerite Prior,  a research associate in Salk's Cellular Neurobiology Laboratory.



The Gist
  • J147 was developed at Salk in the laboratory of David Schubert, a professor in the Cellular Neurobiology Laboratory.
  • He and his colleagues bucked the trend within the pharmaceutical industry, which has focused on the biological pathways involved in the formation of amyloid plaques, the dense deposits of protein that characterize the disease.
  • Instead, the Salk team used living neurons grown in laboratory dishes to test whether their new synthetic compounds, which are based upon natural products derived from plants, were effective at protecting brain cells against several pathologies associated with brain aging.
  • From the test results of each chemical iteration of the lead compound, they were able to alter their chemical structures to make them much more potent. Although J147 appears to be safe in mice, the next step will require clinical trials to determine whether the compound will prove safe and effective in humans.

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Highlights
  • To test the efficacy of J147 in a much more rigorous preclinical Alzheimer's model, the Salk team treated mice using a therapeutic strategy that they say more accurately reflects the human symptomatic stage of Alzheimer's. Administered in the food of 20-month-old genetically engineered mice, at a stage when Alzheimer's pathology is advanced, J147 rescued severe memory loss, reduced soluble levels of amyloid, and increased neurotrophic factors essential for memory, after only three months of treatment.
  • In a different experiment, the scientists tested J147 directly against Aricept, generically known as donepezil, the most widely prescribed Alzheimer's drug, and found that it performed as well or better in several memory tests.
  • The researchers found that while both drugs (J147 and Aricept) improved short-term memory, only J147 improved spatial memory. They also found combining the drugs worked better than either alone.
  • The strategy of using mice with existing disease and the drug discovery process based upon aging are what make the study interesting and exciting. According to David Schubert, "this more closely resembles what happens in humans, who have advanced pathology when diagnosis occurs and treatment begins." Most studies test drugs before pathology is present, which is preventive rather than therapeutic and may be the reason drugs don't transfer from animal studies to humans.
  • The compound, derived from the curry spice component curcumin, has low toxicity and actually reverses damage in neurons associated with Alzheimer’s.
  • J147’s ability to reverse cellular damage and low toxicity puts it in a different class from all other Alzheimer drugs. The ability to repair neuronal damage may make J147 useful in treating other neurodegenerative diseases.
  • The Salk researchers say that J147, with its memory enhancing and neuroprotective properties, along with its safety and availability as an oral medication, would make an "ideal candidate" for Alzheimer's disease clinical trials. They are currently seeking funding for such a trial.

The work was supported by the Alzheimer's Drug Discovery Foundation, the Bundy Foundation, the Fritz Burns Foundation, the George E. Hewitt Foundation, the Alzheimer's Association, and the National Institutes of Health.

About the Salk Institute for Biological Studies

The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment.
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