. Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener. 2013;8:18. PubMed.

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  1. This study by LaClair et al. is one of several studies coordinated by Sangram Sisodia. First and foremost, the principal conclusion, highlighted in the title, is that bexarotene did not improve cognition. However, the data clearly demonstrate that the authors could not detect a transgene-dependent impairment in fear conditioning in the APP/PS1 mice. Since there was no transgene effect on behavior, no conclusions about any possible drug effect can be drawn—period. They state that "freezing behavior may not be a robust or reliable measure of cognitive deficits in this mouse model." This is a remarkable conclusion. The analysis of fear conditioning in this mouse model is a standard measure of cognition and there are many published reports using this assay in these mice. It is difficult to understand how this routine and highly reproducible behavioral assay failed.

    Wong and colleagues used the same unconventional formulation of bexarotene used by Sisodia's group (see Veeraraghavalu et al., 2013) and by Price et al. (see Price et al., 2013). This is an FDA-approved drug with an extensive literature on rodents and it is clear that these researchers (and others) did not investigate standard practices for the formulation and use of bexarotene. Such data was readily available. In our paper, we directly stated that bexarotene was suspended in water and administered by gavage. It is no coincidence that the groups that published negative findings employed a different drug formulation, dissolving it in organic solvents. Thus, it is incorrect to characterize these studies as ‘replication.’

    These authors also misstate and mischaracterize our published data. They state that fear conditioning was the only assay used in APP/PS1 mice by Cramer et al. (see Cramer et al., 2013 ). This is wrong. We monitored behavior using both fear conditioning and the Morris water maze in this strain of mice. Furthermore, they state that Fitz et al. (Fitz et al., 2013) used only the radial arm water maze. This is inaccurate as Fitz et al. also reported that bexarotene improved novel object recognition. LaClair and colleagues also fail to cite findings reported by Tesseur et al. that bexarotene improved behavior in passive avoidance assays (see Tesseur et al., 2013). These data clearly support our conclusions that bexarotene improves memory and cognition. LaClair and colleagues selectively summarize behavior in their table only within the context of fear conditioning.

    Similarly, they fail to note that Fitz et al. reported that bexarotene reduced interstitial fluid levels of soluble Aβ peptides. It should be noted that David Holtzman's group just published a paper reporting that bexarotene rapidly elevates ApoE-based high-density lipoproteins in the interstitial fluid, which correlated with a reduction in ISF Aβ levels (Ulrich et al., 2013). Moreover, at the AD/PD meeting in Florence, and at the June ApoE meeting in Washington, D.C., Danny Michaelson's group in Tel Aviv reported a broad range of salutary effect in ApoE3/4 knock-in mice, including improved behavior. At this meeting Pasinetti and colleagues reported that a different RXR agonist resulted in enhance amyloid clearance and improved behavior in another AD model.

    References:

    . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-f. PubMed.

    . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-d. PubMed.

    . ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012 Mar 23;335(6075):1503-6. PubMed.

    . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-c. PubMed.

    . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-e. PubMed.

    . In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener. 2013;8:13. PubMed.

  2. Since the introduction of a novel approach, such as the use of the RXR agonist bexarotene to counteract AD pathology, often brings controversy, it is important to identify consensus observations that ensue. A key finding from the Landreth group (Cramer et al., 2012), which has now been reproduced by several laboratories, is that bexarotene reduces the level of soluble Aβ in the brain. In contrast, the corresponding finding that bexarotene reduces the levels of Aβ plaques has now been challenged by several groups, including, as outlined in this paper, the Wong laboratory. Without measuring the effect of bexarotene on soluble Aβ, the authors' report that the RXR agonist has no effect on plaques may create the false impression that the metabolism of Aβ is unaffected by bexarotene. It should also be noted that the basal behavioral performance of the APP/PS mice in this paper was similar to the vehicle-treated wild–type control and that neither were significantly affected by bexarotene (Fig. 3 in LaClair et al). Accordingly, since APP/PS mice did not exhibit a cognitive deficit, the summarizing statement in the abstract that the drug failed to attenuate the cognitive deficits of the APP/PS mice is not justified.

    Since bexarotene can stimulate the expression of ApoE lipidating enzymes ABCA1 and ABCG1 and other RXR-regulated genes in addition to ApoE, the physiological consequences of this drug are expected to depend on context. Accordingly, elevation of ApoE levels may be beneficial for mice that express mouse ApoE or human ApoE3, but not those expressing human ApoE4. In addition, increasing lipidation may be effective only when provided to a system that is under-lipidated. The relative contribution of RXR-mediated processes cannot be readily predicted a priori. For example, we reported at the AD/PD meeting in Florence, Italy, last March that the main effect of bexarotene in ApoE4- and ApoE3-targeted replacement mice is to increase the levels of the lipidation enzymes ABCA1 and ABCG1 without significantly affecting the levels of brain ApoE4 or ApoE3, and that this is associated with reversal of key brain phenotypes.

    I believe that experiments with RXR ligands such as bexarotene open a new approach to the ApoE field. Accordingly, it is important to ensure that any controversies in this regard will not lead us to throw the baby out with the bath water.

    References:

    . ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012 Mar 23;335(6075):1503-6. PubMed.

  3. The article by La Clair et al. adds new controversy to the story of bexarotene. This time it surrounds the effect of bexarotene on behavior. Their data demonstrate that the drug did not improve the memory deficits as seen by testing in a fear-conditioning paradigm.

    We would like to make several notes regarding the misrepresentations of the data published by our group (Fitz et al., 2013). In the paper's discussion, La Clair et al. state: “In APPswe/PS1ΔE9 mice with APOE3/4 knock-in, bexarotene was reported to rescue deficits in the Radial Arm Water Maze at 7 months of age, but this testing was also performed on mixed gender cohorts of n=5 per group, introducing a potential false positive treatment effect.”

    First, the number of mice we used for behavior testing was actually higher than the number claimed by LaClair et al. (n=8-13).

    Second, we specifically stated in the text of our paper that the effect was the same in males and females. Third, we presented the data for behavior testing separately for both genders as supplemental information for the reviewers; however, these data were not published in the final version because of space limitations. This information is posted on our Web page and could be examined by readers.

    We would like to comment on the interpretation of bexarotene effects on so-called “soluble” and “insoluble” Aβ. Normally, Aβ species are divided into “soluble” and “insoluble” depending on the protocol used to homogenize the brain postmortem. I would argue that homogenizing brain tissue postmortem cannot ensure the exact separation of plaque-associated Aβ from soluble Aβ. Because of this, there is always some contamination of “soluble Aβ” with plaque-associated Aβ. Therefore, we believe that using microdialysis to sample interstitial fluid of living mice is the only reliable measure of soluble Aβ.

    References:

    . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013 May 24;340(6135):924-c. PubMed.