Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models” by Ashleigh R. Price, Guilian Xu, Zoe B. Siemienski,

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Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models” by Ashleigh R. Price, Guilian Xu, Zoe B. Siemienski, Lisa A. Smithson, David R. Borchelt, Todd E. Golde, and Kevin M. Felsenstein Science Volume 340(6135):924-924 May 24, 2013 Published by AAAS

Fig. 1 Aβ levels and plaque burden are unchanged by bexarotene treatment.APP/PS1ΔE9 mice (7 and 11 months old, including both male and female; n = 5 to 6 per treatment group) were dosed with bexarotene (100 mg/kg per day) or vehicle by oral gavage for 7 days. Aβ levels and plaque burden are unchanged by bexarotene treatment.APP/PS1ΔE9 mice (7 and 11 months old, including both male and female; n = 5 to 6 per treatment group) were dosed with bexarotene (100 mg/kg per day) or vehicle by oral gavage for 7 days. Upon harvest, one hemibrain was frozen in liquid nitrogen, with the other fixed in 4% paraformaldehyde with 0.1 M phosphate buffer, pH 7.6, for histological analysis. (A) The frozen hemibrains were sequentially extracted essentially as previously described (9), using RIPA detergent followed by 2% SDS followed by 70% formic acid. The resulting extracts were analyzed for soluble and insoluble Aβ40 and Aβ42 by differential enzyme-linked immunosorbent assay. Bexarotene and vehicle treatment is shown by the black and gray bars, respectively. (B) Representative cortical sections of bexarotene- or vehicle-treated mice stained with thioflavin S (inset represents magnified image of a typical plaque). (C) Images of sections immunostained with panAβ1-16 antibody 33.1.1 (15); similar results are also seen by silver staining, antibody 6E10, or an Aβ42-specific antibody (data not shown). (D) Quantitation of the plaque numbers. The fluorescent images were scanned using a ScanScope FL (Aperio Technologies). The cortex was outlined, and the numbers of amyloid plaques per mm2 of the cortex were manually counted by an observer blinded to treatment. 7-month-old vehicle-treated = 26.8 ± 4.2 plaques; 7-month-old bexarotene-treated = 19 ± 5.6; 11-month vehicle-treated = 54.8 ± 7.3; 11-month bexarotene-treated = 59.3 ± 7.7; error bars, mean ± SEM; no statistical significance between the groups by Student’s t test. The Aβ burden as percentage of total area was determined using the ImageScope program and Positive Pixel Count Algorithm (Aperio Technologies) from antibody 33.1.1 stained sections (using the average of three sections per brain 30 μm apart), with no statistical significance between the groups. 7-month-old vehicle-treated = 1.0 ± 0.6; 7-month-old bexarotene-treated = 0.7 ± 0.35; 11-month-old vehicle-treated = 2.3 ± 0.8; 11-month-old bexarotene-treated = 2.1 ± 0.8. Ashleigh R. Price et al. Science 2013;340:924 Published by AAAS

Fig. 2 Short-term bexarotene treatment stimulates the expression of LXR target genes in vivo.Brain homogenates from the 11-month-old bexarotene- and vehicle-treated (n = 5 mice) animals made in RIPA lysis buffer were analyzed on Western blot and probed with an antibody specific either for apoE or for ABCA1, along with an internal control for actin. Short-term bexarotene treatment stimulates the expression of LXR target genes in vivo.Brain homogenates from the 11-month-old bexarotene- and vehicle-treated (n = 5 mice) animals made in RIPA lysis buffer were analyzed on Western blot and probed with an antibody specific either for apoE or for ABCA1, along with an internal control for actin. Proteins were quantitated and normalized to actin using an Odyssey LiCor Imager, with results summarized in the accompanying graph. Also shown are the change in liver weights of the two groups (Student’s t test; error bars, mean ± SEM, **P < 0.01, ***P < 0.001). Similar results were seen with the 7-month-old animals; data not shown. Ashleigh R. Price et al. Science 2013;340:924 Published by AAAS