Move over, β amyloid. Here comes apolipoprotein E—target of a potential new Alzheimer’s disease therapy that looks promising in mice. In an online Science paper published yesterday and covered widely in the lay media (see, e.g., National Public Radio; BBC News; The Wall Street Journal), Gary Landreth of Case Western Reserve University, Cleveland, Ohio, and colleagues report that AD mouse models rapidly clear amyloid-β and regain cognitive function when given an approved cancer drug that enhances production of endogenous ApoE.
ApoE transcription is stimulated by retinoid X receptor (RXR) heterodimers formed with either peroxisome proliferator-activated receptor γ (PPARγ) or liver X receptors (LXRs). Prior work shows that PPARγ and LXR agonists improve Aβ pathology and symptoms in AD mice (see Donkin et al., 2010; ARF related news story on Jiang et al., 2008; Heneka and Landreth, 2007). In the Science report—the formal publication of data Landreth presented at an ApoE symposium in Chicago last summer (see ARF related conference story)—first author Paige Cramer and colleagues hit both RXR-PPARγ and RXR-LXR pathways with a single compound—the RXR agonist bexarotene. This is a drug approved by the U.S. Food and Drug Administration to treat certain kinds of skin cancer caused by T cells.
Landreth’s team gave the RXR agonist orally to APP/PS1 mice at two, six, or 11 months of age. Using in-vivo microdialysis—a method pioneered by coauthor John Cirrito at Washington University School of Medicine in St. Louis, Missouri—the researchers saw a dip in soluble Aβ levels in brain interstitial fluid (ISF) of two-month-old APP/PS1 mice as soon as six hours post-treatment. By 24 hours, ISF Aβ42 dropped by 25 percent and remained so for more than 70 hours. The compound spurred a similar Aβ decrease in wild-type mice, but had no influence on ISF Aβ in ApoE-deficient animals, suggesting that ApoE is required for the Aβ-lowering effect.
Brain Aβ deposition typically shows up in these APP/PS1 animals at around six months of age, and here there were benefits, too, with mice showing less soluble and insoluble Aβ by ELISA, and fewer plaques in thioflavin S-stained hippocampus and cortex. Moreover, longer treatment (20-90 days) improved contextual fear conditioning and Morris water maze performance in APP/PS1 mice as well as in a transgenic APP mouse with more aggressive pathology (APPPS1-21). When given to Tg2576 mice, the compound helped restore social behavior such as nest-building—an ability that fades progressively in this AD strain (Wesson and Wilson, 2011), and sense of smell, which also wanes in Tg2576 mice. Odor-guided behaviors rely on neural networks in the piriform cortex (PCX) circuit, and disruptions in this circuit have been linked to olfactory impairment in AD patients and Tg2576 mice (Wesson et al., 2011). In the current work, Landreth and colleagues found aberrant PCX network activity in vehicle-treated Tg2576 mice, which returned to normal with three days of bexarotene. The Aβ pathology and behavioral changes were all accompanied by increased expression of ApoE, and other RXR-inducible genes, as measured by Western blots.
The study demonstrates that “an FDA-approved drug reduces amyloid burden in a spectacularly rapid and robust fashion. I have not seen something this exciting since the amyloid vaccine papers,” noted Steve Estus of the University of Kentucky in Lexington. “The FDA approval is key because this indicates that the drug has an acceptable safety profile, at least for limited use in humans.”
Based on their findings in AD mice, Landreth and colleagues plan to launch a Phase 1b biomarker trial of bexarotene in normal adults, looking for falling Aβ and rising ApoE levels in cerebrospinal fluid after treatment. The trial should start in the next few months and be finished by summer, Landreth told ARF. His team will collaborate with St. Louis-based C2N Diagnostics, a company founded to commercialize a method Randy Bateman and other WashU researchers developed to monitor Aβ synthesis and clearance in real time in human CSF (see ARF related news story).
One concern with LXR/RXR agonists is that they not only drive up transcription of ApoE and its transporters (such as ATP-binding cassette transporter, aka ABCA1), but also upregulate genes associated with fatty acid synthesis. This off-target effect has halted clinical development of LXR-targeted compounds, noted Kelly Bales of Pfizer Global Research and Development, Groton, Connecticut. At a recent ApoE workshop held at the Gladstone Institute of Neurological Disease in San Francisco, Bales reported on her team’s studies with other small molecules that drive up brain ApoE levels in AD mice.
Meanwhile, researchers led by Vijayalakshmi Ravindranath at the National Brain Research Centre in Haryana, India, have gone au naturel—reducing Aβ pathology and behavioral deficits in AD transgenic mice with extracts from an Indian ginseng (Withania somnifera). Surprisingly, the compound worked by boosting expression of low-density lipoprotein receptor-related protein (LRP) in the liver. (Brain LRP binds ApoE and helps regulate Aβ clearance.) These effects—reported online January 30 in the Proceedings of the National Academy of Sciences USA (Sehgal et al., 2012)—suggest it may be possible to develop AD therapeutic compounds that promote Aβ clearance without actually entering the brain.—Esther Landhuis
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