23 December 2011. Research hints that a curry spice derivative might be a potential treatment for Alzheimer's disease and other neurodegenerative disorders. The compound—known as J147—enhances memory in both normal and transgenic mice, and provides a variety of anti-aging benefits. The product of over a decade of work by David Schubert of the Salk Institute in La Jolla, California, J147 reduces oxidative stress and inflammation, enhances long-term potentiation, and lowers amyloid plaques in animals. It also gets into the brain more easily and is more resistant to metabolism than the original curry spice curcumin. If proven safe and effective in humans, J147 could provide a non-Aβ-centric method of treatment for AD, suggest the authors.
J147 has “the potential to be an AD therapeutic by slowing disease progression through neuroprotection as well as providing immediate cognition benefits," wrote the authors in the paper published in the December 14 issue of PLoS ONE.
First author Qi Chen and colleagues knew that curcumin had long been examined as a potential Alzheimer's treatment. It reportedly reduces oxidative damage and inflammation (see ARF related news story on Lim et al., 2001), prevents Aβ aggregation (see ARF related news story on Yang et al., 2004), and promotes neurogenesis (see ARF related news story on Kim et al., 2008) in mice. Curcumin is now in Phase 2 clinical trials to see if the compound slows cognitive decline in people with memory complaints. However, curcumin does not penetrate to the brain very easily and breaks down quickly, so Schubert and his team sought to modify the compound to bestow it with better medicinal qualities.
A few tweaks of curcumin's chemistry led first to a hybrid molecule, CNB-001, with characteristics of the neurotrophic molecule cyclohexyl-bisphenol A (see Liu et al., 2008). CNB-001 was more stable and neuroprotective than curcumin, but it still could not enter the brain very easily. Further tinkering led to the more potent J147, which readily penetrated the brain and, like its precursor molecules, had pleiotropic effects on aging and neurodegenerative pathways. In the current study, Chen found that in cultured rat cortical neurons, J147 protected against oxidative stress, amyloid toxicity, trophic factor withdrawal, glucose starvation, and ischemia. In rat hippocampal slices, J147 induced long-term potentiation (a model of memory formation on the cell level) when the slices were given weak titanic pulses. In cell culture, in rats, and in transgenic mice, it boosted brain-derived neurotrophic factor (BDNF)—necessary for neuron survival, and often reduced in neurological disorders. J147 also worked in cells that lacked BDNF receptors, hinting that the compound modifies downstream targets of BDNF. Unlike curcumin and CNB-001, J147 did not inhibit Aβ42 aggregation.
The team then tested the compound's memory-enhancing qualities in normal animals. In seven-week-old Sprague-Dawley rats, J147 was given orally one hour before habituation improved memory in a novel object recognition test. Likewise, two weeks of J147-spiked chow improved mouse performance on the novel object location test, Y maze, and Barnes maze tests, meaning improvements on spatial, short-term, and working memory in wild-type rodents.
But what about transgenic mouse models? The team began feeding four-month-old APPswe/PSEN1ΔE9 mice with J147 chow. After five months on the diet, mice that received the supplement outperformed transgenic controls by acquiring and remembering the platform location in the Morris water maze test just as well as non-transgenic mice. J147-fed transgenics accumulated less soluble Aβ40 and Aβ42 in their hippocampi relative to mice on a normal diet. Heat-shock proteins, which are markers of oxidative stress, dropped in the hippocampi as well, and several synaptic proteins, including synapsin and synaptophysin, that are lost in AD and in this transgenic model were back to control levels.
"What's interesting about this approach is that it's both cognitive enhancing and disease modifying," said Greg Cole, University of California, Los Angeles. Cole’s group has pioneered studies on curcumin in AD. While curcumin might eventually prove to be better for prevention because of its anti-Aβ aggregation properties, the dual effect of J147 might work better for later stages of the disease. "If you're looking at people with pathology, then it makes sense to use something like J147." He added that he would have liked to see how the compound performed in a tau transgenic model.
Due to its general neuroprotective properties, J147 might be effective against other neurodegenerative diseases such as Parkinson's and Huntington's, said Schubert. "Most of the cell death pathways associated with these neurodegenerative conditions are essentially the same," he said. "The type of drug that we're dealing with is neuroprotective, rather than just targeting the amyloid pathway."
The team is currently trying to work out how the drug works. Meanwhile, the next step is to get J147 into clinical trials in people to test safety, said Schubert. He is applying for grants that would provide the necessary funding.—Gwyneth Dickey Zakaib.
Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, Chiruta C, Akaishi T, Abe K, Maher P, Schubert D. A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer’s Disease. PLoS ONE. 2011 December; 6(12). Abstract