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LEARNING AN OLD DRUG’S NEW TRICKS
activate proteins called nuclear receptors. Bexarotene activates a pair of these receptors—one being a retinoid X receptor— which in turn switch on a gene that makes apolipoprotein E (ApoE). When combined with fatty compounds called lipids, ApoE forms spongelike globs thought to soak up Researchers seek mechanism for cancer drug and clear toxic compounds from the body. bexarotene’s alleged ACTIVITY AGAINST ALZHEIMER’S Landreth guessed bexarotene might help LAUREN K. WOLF, C&EN WASHINGTON wipe amyloid plaques from the brain by increasing ApoE’s production. When other teams didn’t see the drug OH clear plaques from their lab animals’ brains, The initial excitement over bexFINDING A NEW PURPOSE for an old O that mechanism was called into question. arotene turned to skepticism a year drug is cause for celebration among Most of today’s Alzheimer’s experts have later, when four research teams pharmaceutical firms and patients set aside the notion that amyloid plaques reported they couldn’t completely alike. Using a compound that’s already are the toxic culprit responsible for the disreplicate the Case Western Reserve been tested for one disease to treat anease, says Jacques Fantini, a biochemist group’s findings (C&EN, June other eliminates steps in the drugOH at Aix-Marseille University, in France. 10, 2013, page 30). Some teams vetting process and potentially They now believe amyloid oligoobserved cognitive improvegets medicine to patients more mers—smaller, water-soluble peptide ments in their bexarotenequickly. aggregates—are responsible. A few of treated mice, but some didn’t. So it’s not surprising that bexthe groups that tried to replicate the And none of the groups saw a dearotene, a molecule approved more original Case Western Reserve study, crease in the plaques riddling than a decade ago by the Food & Bexarotene in fact, did see a decrease in this type their rodents’ brains. Drug Administration for treating of soluble amyloid in their mice. In the wake of the confusion, rea form of lymphoma, made headlines in Landreth has also shifted his prosearchers have been taking a closer early 2012 when it showed promise as posed mechanism’s emphasis slightlook at how bexarotene might work—if a treatment for Alzheimer’s disease. A ly, suggesting that bexarotene helps at all—in nerve cells. Some scientists research team led by Gary E. Landreth of remove amyloid oligomers, rather than have collected data that jibe with Case Western Reserve University School amyloid plaques, from the brain. the mechanism originally proposed of Medicine demonstrated that bexarotene Looking for an alternative explanaby Landreth. Others are proposing could clear amyloid plaques—the clumps tion, Fantini recently noticed bexaroa radically different way the drug of misfolded peptide that are a hallmark of Cholesterol tene’s structural similarity to cholesmight work. Alzheimer’s—from the brains of lab mice. terol, another molecule that’s been linked Landreth’s original rationale for pitThe drug also appeared to restore the roto Alzheimer’s. People with higher levels ting bexarotene against Alzheimer’s is dents’ memory (Science 2012, DOI: 10.1126/ of “bad” cholesterol, or LDL, are at higher the compound’s ability to bind to and science.1217697).
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SOME EXPERTS THINK amyloid oligomers are toxic because they damage nerve cells by punching holes in them. They hypothesize that amyloid peptides insert into nerve cell membranes, stick together, and make pores, Fantini says. These pores have been observed in artificial membranes in the lab and even in the brain tissue of deceased patients. Fantini’s research group modeled the pores and their interaction with cholesterol using computer simulations (ACS Chem. Neurosci. 2014, DOI: 10.1021/cn400183w). The scientists found, at least in models, that cholesterol helps stabilize pores made of amyloid. To confirm these results, the team added amyloid peptide to brain-derived cells. The researchers then measured pore formation by looking at whether calcium surged into the cells—something that happens when neurons are damaged in Alzheimer’s. They observed a flux, but only from cells with sufficient levels of cholesterol. More important, when Fantini’s group added bexarotene, ions stopped rushing into the cells. They took that result as a sign that the compound disrupts cholesterol’s interaction with amyloid and destabilizes the pores. “My main purpose in carrying out this
researchers wanted to find study was not to prove molecules that would actithat bexarotene is a vate a nuclear receptor good candidate for called Nurr1 because treating Alzheimer’s,” it maintains the health Fantini emphasizes. of dopamine-producing “We are looking for nerve cells—those typimechanisms.” If valid, cally damaged in Parkinthough, his pore hypothson’s disease. When the reesis might lead to a rational searchers screened a library of strategy for discovering compounds, bexarotene came Alzheimer’s drugs—ones that up as a “hit,” activating Nurr1 PERFECT PORE inhibit the interaction between in conjunction with a retinoid cholesterol and amyloid, he says. In this molecular model of an amyloid X receptor. According to James S. Nopore, the peptides The Acadia team gave bexwick, a chemist at the Univerare green, red, arotene to rats with damaged sity of California, Irvine, the blue, and gray, and cholesterol is yellow. dopamine neurons for 28 days. mechanism put forth by FanNot only did the rodents’ motor tini’s team is intriguing. But he skills and cognition improve, wonders whether bexarotene is but a significant number of the animals’ exerting its effects by binding to calcium dopamine-producing nerve cells became rather than to amyloid. Unlike cholesterol, functional (ACS Chem. Neurosci. 2013, DOI: bexarotene contains a carboxylic acid, 10.1021/cn400100f ). which interacts with calcium ions strongly, The Acadia researchers say these experihe points out. “The resemblance between ments can’t determine whether the activacholesterol and bexarotene may be more tion of nuclear receptors alone accounts superficial than the authors anticipate,” for all the positive effects they observed. Nowick contends. Fantini takes a similar view: “Bexarotene Case Western Reserve’s Landreth says likely has multiple activities, and one the pore idea “is not entirely implausible,” mechanism does not exclude the others.” but he sticks by his original mechanism, While researchers try to better underpointing to a bexarotene study published stand a drug that’s stirred up intrigue and in October of last year. consternation in the research community, The experiment, carried out by Acadia clinical trials continue. Landreth says a Pharmaceuticals, in San Diego, demonPhase Ib trial of bexarotene now under way strated that low doses of bexarotene helped in cognitively normal patients should help rats with symptoms of Parkinson’s disease, determine the drug’s mechanism. ◾ another neurodegenerative condition. The
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risk of Alzheimer’s than those with normal levels, scientists have shown (JAMA Neurol. 2013, DOI: 10.1001/jamaneurol.2013.5390). Fantini had already been investigating one way cholesterol might contribute to Alzheimer’s: through amyloid pores.
