Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models"

Abstract

Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) demonstrated in a mouse model for Alzheimer's disease (AD) that treatment of APP/PS1ΔE9 mice with bexarotene decreased Aβ pathology and ameliorated memory deficits. We confirm the reversal of memory deficits in APP/PS1ΔE9 mice expressing human APOE3 or APOE4 to the levels of their nontransgenic controls and the significant decrease of interstitial fluid Aβ, but not the effects on amyloid deposition.

Figure 1. Bexarotene restores cognitive function and decreases ISF Aβ level in APP/E3 and APP/E4 mice

A, B and C, APP/E3 and APP/E4 mice (7 months old) and matched non-transgenic littermates (E3 and E4) were treated with bexarotene or vehicle. N=8-13 mice per group (male and female). RWM (7) was used to assess bexarotene effect on spatial learning deficits in APP/E3 (A) and APP/E4 mice (B). Analysis by two-way repeated measures ANOVA shows a significant effect on treatment (p<0.0001) and training (p<0.001) in both APOE isoforms. Tukey’s posttest shows that bexarotene treated APP mice were significantly different from vehicle treated APP mice (p < 0.05 for both APOE isoforms) but not different from their non-transgenic controls. C. Novel object recognition test was performed on the same mice following RWM. Analysis by one-way ANOVA and Tukey’s post hoc test shows that bexarotene treated APP mice were significantly different from vehicle treated APP mice (p < 0.001 for both isoforms) but not from their non-transgenic controls. D. Bexarotene treatment significantly decreases Aβ level in ISF. APP/E3 and APP/E4 mice (3.4 month old) were treated with 100 mg/kg bexarotene for 48 hours and in vivo microdialysis was performed in the hippocampus as in (7). ISF A β 40 and A β 42 were determined by ELISA. Analysis by t-test; N=5 male and female mice per group.

Figure 2. Bexarotene treatment does not affect amyloid deposition

Following the behavior tests the levels of amyloid plaques, soluble and insoluble Aβ and soluble oligomers were compared in 7 month old APP/E3 and APP/E4 (comparable number of male and female). A. Results of X-34 staining of compact fibrillar amyloid plaques in cortex and hippocampus (7). Representative pictures for X-34 (20X) are shown on the right. B. Results of anti-A β antibody staining of brain sections. For A and B, N=8-12 mice per group. C, D and E, ELISA results for insoluble Aβ40 and Aβ42 in cortex (C) and hippocampus (D), and soluble Aβ in cortex (E). N=9-17 mice per group. F. Bexarotene treatment significantly decreased A11-positive oligomers (4). Intensity of the dots were quantified and normalized on the total protein measured on dot blots stained with coomassie blue. N=7-9 mice. For all panels analysis is by t-test.