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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.
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Tel Aviv University
The pivotal publication from the Landreth group that the RXR agonist and anti-cancer drug bexarotene lowers the levels of Aβ in vivo and that this is associated with increased levels of ApoE (Cramer et al., 2012) paved the way for a new therapeutic approach to AD and simultaneously raised important questions. This paper from the LaDu group addresses these issues and extends them in an important way.
The original Landreth study was performed with mice that express mouse ApoE (mApoE) and human Aβ (hAβ). However, the situation becomes theoretically more complicated in the case of human ApoE, because bexarotene could theoretically have opposing effects. Namely, upregulation of the expression of human ApoE, including ApoE4, which is the most prevalent risk factor of AD, could induce pathology, whereas upregulation of the ApoE lipidating protein ABCA1, which is also regulated by the RXR system, could theoretically be beneficial. Anat Bohem-Cagan from our group addressed this question recently utilizing mice that express human ApoE4 and ApoE3 and mouse Aβ. This revealed that bexarotene reverses key brain pathological and cognitive impairments that are induced by ApoE4 and that biochemically this is associated with reversal of the hypolipidation of ApoE4 and with no changes in ApoE4 levels (Boehm–Cagan et al., 2014). One of the ApoE4-driven phenotypes that was reversed by bexarotene in our study was the accumulation of Aβ in hippocampal neurons; however, this was performed on mice expressing only endogenous Aβ.
In the present study from Tai and colleagues in the LaDu group, the authors developed and utilized a new, powerful, double-transgenic mouse system, which expresses human APP/Aβ and human ApoE3 or ApoE4, to study the effects of bexarotene on a background of human Aβ and human ApoE. They revealed that bexarotene increases the levels of ABCA1 and the lipidation of ApoE in these animals, and demonstrated that the latter results in an increased level of ApoE4/Aβ complex, which in turn leads to decreased levels of oligomeric Aβ. Since oligomeric Aβ is a key pathological player, this provides a novel mechanism whereby the pathological effects of ApoE4 are counteracted by bexarotene. Interestingly, the study also showed that the effects of bexarotene are brain-area-specific and are more pronounced in the hippocampus than the cortex.
Importantly, bexarotene was efficacious when administered for seven days, but had no effect when over 30 days. Further studies are required to unravel the mechanisms underlying this effect and for the development of efficacious chronic treatments with bexarotene.
References:
Boehm-Cagan A, Michaelson DM. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J Neurosci. 2014 May 21;34(21):7293-301. PubMed.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012 Mar 23;335(6075):1503-6. Epub 2012 Feb 9 PubMed.
University of Pittsburgh
In this study, Tai et al. explore the effect of two RXR agonists (bexarotene and LG100268) on amyloid pathology of APP transgenic mice (5XFAD) expressing human ApoE isoforms. Authors used short (seven days) and long (30 days) treatments to test the effect on Aβ and ApoE level. As a result of the short treatment they found an increase in ApoE protein level and a decrease of soluble Aβ and Aβ oligomers in a TBS-X-extracted fraction of the hippocampus of E4FAD mice. Unexpectedly, the opposite effects were observed in the cortex of E4FAD and E3FAD mice. Notably, in this AD model the major anatomical region of Aβ accumulation is the hippocampus, which incidentally has a higher ApoE protein level. Surprisingly, no effect on Aβ or other markers were found in the hippocampus of E3FAD mice. Since ApoE level in E4FAD is lower than in E3FAD mice, the authors argue that RXR agonists may elicit beneficial effects only when lipidated ApoE falls below some critical pathological threshold, as for example in E4FAD mice. The conclusion is that in the hippocampus RXR agonists increase ApoE lipidation and the formation of ApoE-Aβ complexes, which in turn decrease Aβ in this region. Such a hypothesis is supported by the finding that there is a negative association between ApoE-Aβ complex and oligomeric Aβ in the hippocampus of E4FAD mice.
The study is interesting in that it helps to understand the effect of RXR agonists on amyloid pathology. However, to some degree it adds to the controversy surrounding the effects of bexarotene. It is important that the authors show an effect on amyloid pathology in AD mice expressing human ApoE4 isoforms, since ApoE4 carriers usually fail to respond to therapy in the ongoing clinical trials. In general the data also agree with published studies showing Bexarotene decreases soluble (Veeraraghavalu et al., 2013; Cramer et al., 2012; Fitz et al., 2013; Boehm-Cagan and Michaelson, 2014) but not insoluble Aβ levels in APP tg mice (Veeraraghavalu et al., 2013; Fitz et al., 2013; Tesseur et al., 2013; Price et al., 2013). Interestingly, Tai et al. confirm our previous finding that Bexarotene decreases the level of soluble Aβ oligomers in the brain of APP mice expressing human APOE3 and E4 isoforms (Fitz et al., 2013). The authors also emphasize the significance of ApoE-Aβ complexes, which was recently questioned by Verghese et al. (Verghese et al., 2013). Finally, as in many studies, there are unanswered questions here as well: What was the effect of RXR ligands on amyloid plaques as detected by immunohistochemistry? Did Bexarotene affect cognitive performance/memory deficits in this AD model and how?
References:
Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, Jucker M, Holtzman DM, Tanzi RE, Vassar R, Sisodia SS. 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.
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012 Mar 23;335(6075):1503-6. Epub 2012 Feb 9 PubMed.
Fitz NF, Cronican AA, Lefterov I, Koldamova R. 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.
Boehm-Cagan A, Michaelson DM. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. J Neurosci. 2014 May 21;34(21):7293-301. PubMed.
Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, Gijsen H, Moechars D, Mercken M, Kemp J, D'Hooge R, De Strooper B. 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.
Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM. 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.
Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C, Holtzman DM. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1807-16. PubMed.
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