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Mitochondria management for Alzheimer's treatment
LA JOLLA, Calif.—Knowing that experimental drugs work isn't enough in pharmaceutical research—it's also important to know how they work, as a drug's mechanism of action can shed light on new targets for diseases. That is the case for J147, a modified version of curcumin, a molecule found in turmeric. Developed in 2011 by a research group led by Dave Schubert, head of the Salk Institute for Biological Studies’ Cellular Neurobiology Laboratory, J147 was the focus of a recent study published in Aging Cell. The study revealed that J147, which has been shown to treat Alzheimer's disease and reverse aging in mice, binds to a protein found in mitochondria and makes aging cells (as well as flies and mice) look younger.
The study, titled “The mitochondrial ATP synthase is a shared drug target for aging and dementia,” explains that J147 was previously discovered through the application of “a unique phenotypic screening paradigm specifically designed to recapitulate several of the most common age-associated central nervous system toxicities using cell culture models (Prior et al., 2014).” J147 was found to be neuroprotective in all of the applied assays, with the authors noting that the compound “promotes the division of neuronal precursor cells in vivo and in vitro (Prior et al., 2016). Behaviorally, it enhances memory and restores cognition in APPswe/PS1ΔE9 and the rapidly aging senescence-accelerated mouse prone (SAMP8) dementia mouse models (Currais et al., 2015; Prior, Dargusch, Ehren, Chiruta, & Schubert, 2013; Morley, Armbrecht, Farr, & Kumar, 2015).”
In this more recent work, scientists identified ATP synthase as J147's molecular target. ATP synthase is a mitochondrial protein that helps generate ATP in mitochondria, and has been shown to moderate aging in C. elegans worms and flies. Manipulating its activity enabled the team to protect neuronal cells from toxicities associated with an aging brain.
“This really glues together everything we know about J147 in terms of the link between aging and Alzheimer’s,” said Schubert, senior author of the new paper. Schubert led the study, along with Salk Research Associate Josh Goldberg, who was first author. “Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials.”
“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke,” he added. “But it may be that by targeting aging, we can treat or slow down many pathological conditions that are old-age-associated.”
Moderating ATP synthase's activity with J147 alters the levels of other molecules, including ATP, resulting in healthier, more stable mitochondria throughout aging and in disease states. Specifically, as noted in the study, “By targeting ATP synthase, J147 causes an increase in intracellular calcium, leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila.”
The authors wrote that “Because J147 was identified based on its ability to protect cells from old age-associated neurotoxicities in vitro, these results strongly imply that aging and age-associated dementia are much more closely related than previously assumed and may share common drug targets. If the close relationship between preventing aging and dementia observed for J147 holds true for other genetic targets identified in aging research, these pathways would provide a new source of AD drug targets that are desperately needed.”
The researchers are now exploring the other molecules affected by J147 administration in an effort to discover new drug targets. As for J147, it has completed U.S. Food and Drug Administration-required toxicology testing in animals, and funding is being pursued for Phase 1 trials in humans.
Other researchers involved with this work were A. Currais, M. Prior, W. Fischer, C. Chiruta, D. Daugherty, R. Dargusch and P. Maher of the Salk Institute; E. Ratliff and K. Finley of San Diego State University; P.B. Esparza-Molto and J.M. Cuezva of the Universidad Autonoma de Madrid; and M. Petrascheck of The Scripps Research Institute.