Researchers identify the molecular target of J147, which is nearing clinical trials to treat Alzheimer's disease

January 9, 2018, Salk Institute
Credit: Salk Institute

The experimental drug J147 is something of a modern elixir of life; it's been shown to treat Alzheimer's disease and reverse aging in mice and is almost ready for clinical trials in humans. Now, Salk scientists have solved the puzzle of what, exactly, J147 does. In a paper published January 7, 2018, in the journal Aging Cell, they report that the drug binds to a protein found in mitochondria, the energy-generating powerhouses of cells. In turn, they showed, it makes aging cells, mice and flies appear more youthful.

"This really glues together everything we know about J147 in terms of the link between aging and Alzheimer's," says Dave Schubert, head of Salk's Cellular Neurobiology Laboratory and the senior author on the new paper. "Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials."

Schubert's group developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule found in the curry spice curcumin. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer's progression in mice. However, they didn't know how J147 worked at the molecular level.

In the new work, led by Schubert and Salk Research Associate Josh Goldberg, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP—the cell's energy currency—within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies.

"We know that age is the single greatest contributing factor to Alzheimer's, so it is not surprising that we found a drug target that's also been implicated in aging," says Goldberg, the paper's first author.

Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules—including levels of ATP itself—and leads to healthier, more stable mitochondria throughout aging and in disease.

"I was very surprised when we started doing experiments with how big of an effect we saw," says Schubert. "We can give this to old mice and it really elicits profound changes to make these mice look younger at a cellular and ."

The results, the researchers say, are not only encouraging for moving the drug forward as an Alzheimer's treatment, but also suggest that J147 may be useful in other age-associated diseases as well.

"People have always thought that you need separate drugs for Alzheimer's, Parkinson's and stroke" says Schubert. "But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated."

The team is already performing additional studies on the molecules that are altered by J147's effect on the mitochondrial ATP synthase—which could themselves be new targets. J147 has completed the FDA-required toxicology testing in animals, and funds are being sought to initiate phase 1 in humans.

Explore further: Experimental drug targeting Alzheimer's disease shows anti-aging effects

More information: The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. DOI: 10.1111/acel.12715

Related Stories

Experimental drug targeting Alzheimer's disease shows anti-aging effects

November 12, 2015
Salk Institute researchers have found that an experimental drug candidate aimed at combating Alzheimer's disease has a host of unexpected anti-aging effects in animals.

Scientists develop drug that slows Alzheimer's in mice

May 13, 2013
A drug developed by scientists at the Salk Institute for Biological Studies, known as J147, reverses memory deficits and slows Alzheimer's disease in aged mice following short-term treatment. The findings, published May 14 ...

Cannabinoids remove plaque-forming Alzheimer's proteins from brain cells

June 29, 2016
Salk Institute scientists have found preliminary evidence that tetrahydrocannabinol (THC) and other compounds found in marijuana can promote the cellular removal of amyloid beta, a toxic protein associated with Alzheimer's ...

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 today in PLoS One.

More evidence shows natural plant compound may reduce mental effects of aging

July 10, 2017
Salk scientists have found further evidence that a natural compound in strawberries reduces cognitive deficits and inflammation associated with aging in mice. The work, which appeared in the Journals of Gerontology Series ...

Healthy mitochondria could stop Alzheimer's

December 6, 2017
Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called ...

Recommended for you

Fetal gene therapy prevents fatal neurodegenerative disease

July 16, 2018
A fatal neurodegenerative condition known as Gaucher disease can be prevented in mice following fetal gene therapy, finds a new study led by UCL, the KK Women's and Children's Hospital and National University Health System ...

New study finds that fat consumption is the only cause of weight gain

July 13, 2018
Scientists from the University of Aberdeen and the Chinese Academy of Sciences have undertaken the largest study of its kind looking at what components of diet—fat, carbohydrates or protein—caused mice to gain weight.

Basic research in fruit flies leads to potential drug for diseases afflicting millions

July 13, 2018
River blindness and elephantiasis are debilitating diseases caused by parasitic worms that infect as many as 150 million people worldwide. They are among the "neglected tropical diseases" for which better treatments are desperately ...

Light based cochlear implant restores hearing in gerbils

July 12, 2018
A team of researchers with members from a variety of institutions across Germany has developed a new type of cochlear implant—one based on light. In their paper published in the journal Science Translational Medicine, the ...

Researchers discover gene that controls bone-to-fat ratio in bone marrow

July 12, 2018
In an unexpected discovery, UCLA researchers have found that a gene previously known to control human metabolism also controls the equilibrium of bone and fat in bone marrow as well as how an adult stem cell expresses its ...

Intensive care patients' muscles unable to use fats for energy

July 12, 2018
The muscles of people in intensive care are less able to use fats for energy, contributing to extensive loss of muscle mass, finds a new study co-led by UCL, King's College London and Guy's and St Thomas' NHS Foundation Trust.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.