The lymphoma drug bexarotene, under cross-examination as an Alzheimer’s therapeutic, dramatically lowers soluble Aβ in mice in some studies but not others. A paper in the September 12 Journal of Biological Chemistry offers an explanation for the discrepancy. Researchers led by Mary Jo LaDu at the University of Illinois at Chicago reported that bexarotene squelched soluble Aβ only in mice that expressed human apolipoprotein E4 (ApoE4), a major Alzheimer’s risk factor, and only in brain regions with extensive amyloid deposits. The authors attribute this to the drug’s ability to stimulate the packing of lipids onto ApoE4. This variant normally hooks less lipid than the other isoforms do, and may clear Aβ ineffectively as a result. In mice carrying human ApoE3, or in brain regions with little amyloid accumulation, bexarotene treatment provided no benefit.
“For ApoE4 carriers who have high Aβ levels, increasing ApoE lipidation may be a promising therapeutic strategy,” first author Leon Tai told Alzforum. Such a strategy might help people at later stages of AD, in contrast to current approaches that focus on prevention, Tai noted.
“The findings are very important,” said Ling Li at the University of Minnesota, Minneapolis. Other commentators agreed. “This is a promising lead that suggests drugs focused on ApoE could be an alternative to Aβ therapies,” said Michael Vitek, founder and CEO of biotech startup Cognosci Inc. in Research Triangle Park, North Carolina, which develops ApoE mimetics.
Bexarotene first attracted the attention of AD researchers when Gary Landreth and colleagues at Case Western Reserve University, Cleveland, Ohio, reported that it rapidly cleared Aβ and improved cognition in AD mice (see Feb 2012 news story). Attempts to replicate the finding met with mixed results, however, with some groups reporting no treatment benefit (see May 2013 news story). A recent study from Daniel Michaelson and colleagues at Tel Aviv University in Israel found that the drug boosted ApoE lipidation in E4 knock-in mice, restoring their cognitive performance and synaptic markers to levels seen in E3 carriers (see May 2014 news story).
LaDu and colleagues wanted to investigate bexarotene’s effect in mice that expressed both human amyloid precursor protein (APP) and ApoE variants. They used transgenic mice, generated by introducing human ApoE isoforms into the 5xFAD model, which develops aggressive amyloid pathology (see Jul 2011 conference story). With Gregory Thatcher, also at the University of Illinois at Chicago, the authors dissolved bexarotene in sesame oil and administered it either by gavage or in the animals’ water supply. Drug formulation had been a sticking point in the interpretation of prior mouse data, but Thatcher’s pharmacokinetic analyses revealed that in either form, bexarotene entered the brain and engaged its targets, the lipidating proteins ABCA1 and ABCG1.
In 6-month-old ApoE4-FAD animals, bexarotene given for a week halved the level of soluble, oligomeric Aβ in the hippocampus, as detected by commercial ELISAs that use an antibody said to be specific for the oligomeric form. Treatment also pumped up lipidation of ApoE4 and increased the amount of Aβ complexed with the lipoprotein, suggesting that ApoE4 could more effectively clear the peptide. In contrast, in 6-month-old ApoE3-5xFAD mice, and in the cortex of E4-5xFADs where Aβ levels were low, the drug did not affect ApoE. Lower Aβ levels in these regions associated with higher ABCA1 and ABCG1 and greater ApoE3 and ApoE4 lipidation. The data implies that as Aβ rises, ApoE lipidation falls, and bexarotene counteracts that. There may be some threshold of ApoE lipidation, above which bexarotene helps no more, the authors suggest.
Surprisingly, for 6-month-old ApoE3 and ApoE4 FAD mice, one week of bexarotene treatment more than doubled the amount of soluble oligomeric Aβ in the cortex. How this detrimental effect comes about is unclear. However, the finding may help explain a discrepancy, LaDu noted. Earlier studies used models in which Aβ levels varied widely from mouse to mouse, and included females, which accumulate more Aβ than males. Therefore, bexarotene’s efficacy may have fluctuated greatly among the animals, canceling out effects in some studies. By contrast, Tai’s study used only male mice from an aggressive model with more uniform amyloid levels, he said.
In a one-month prevention study in younger animals, the authors saw no benefit from bexarotene. When treatment started at five months, neither ApoE lipidation nor soluble Aβ budged in either mouse model or brain region. Bexarotene is known to damage the liver, which roughly doubled in size in these animals. Since other studies have shown that liver toxicity can stress the central nervous system, perhaps this underlies the drug’s lack of efficacy during longer-term treatment, the authors speculated. “We think this indicates that systemic, off-target effects might be doing something harmful,” Tai said.
Bexarotene binds and activates nuclear transcription factors called retinoid X receptors, but also affects other nuclear receptors. The bexarotene analogue LG100268 binds more selectively to RXRs. Tai and colleagues tested it as well, but obtained identical results to bexarotene, suggesting that any RXR agonist might share similar problems. “We need to address these negative side effects of RXR agonists before we proceed to a clinical trial,” Tai said.
To other researchers, this study implies that the ApoE4 allele represents a loss of function. If so, raising ApoE levels or otherwise restoring its activity would be therapeutic. The field still debates this issue, as other work suggests lowering ApoE as the better strategy (see Apr 2013 news story).
The paper raises new questions, Li noted. Is the disparity between bexarotene’s effects in the hippocampus and cortex due to amyloid pathology, or regional brain differences? ABCA1 and ABCG1 may be regulated differently in distinct regions, she noted. Does bexaroten affect other lipoproteins, such as ApoA1 (see Oct 2010 news story) or ApoJ (clusterin, currently No. 3 on AlzGene)? It would be interesting to directly measure Aβ clearance through the interstitial fluid and look at bexarotene’s effects on behavior in these mice, Li suggested.
Landreth said that the findings largely agree with previous work on bexarotene. “This is an interesting and provocative study that sheds new light on the complexities of drug action in the AD brain,” he told Alzforum. He noted that bexarotene is less toxic in people than in mouse models, and is given at lower doses. Liver enlargement occurs transiently in people, and the Food and Drug Administration has not recorded any central nervous system side effects in the tens of thousands of people who have taken this drug to combat skin cancer, he said. Landreth is wrapping up sample collection in a Phase 1b trial that examines the effect of the drug on ApoE and Aβ levels over 72 hours in healthy volunteers. A Phase 2 study of bexarotene in AD patients is ongoing at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas.—Madolyn Bowman Rogers
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Research Models Citations
- Averting a Late-life Crisis: Midlife ApoE2 Clears Plaques in Mice
- Could Bexarotene Treat Parkinson’s Disease?
- Can Cancer Therapy Be Neurodegenerative Wonder Drug?
- ApoE4 Promotes Aβ Oligomerization
- Keystone: Symposium Emphasizes Key Aspects of ApoE Biology
- San Francisco: Tweaking Brain ApoE Reduces Aβ, Symptoms
- ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology
- Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, Ben Aissa M, Thatcher GR, LaDu MJ. Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J Biol Chem. 2014 Oct 31;289(44):30538-55. Epub 2014 Sep 12 PubMed.