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. 2015 Nov 10:3:70.
doi: 10.1186/s40478-015-0250-y.

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models

Fan Liao  1 , Tony J Zhang  1 , Hong Jiang  1 , Katheryn B Lefton  1 , Grace O Robinson  1 , Robert Vassar  2 , Patrick M Sullivan  3   4 , David M Holtzman  5
Affiliations

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models

Fan Liao et al. Acta Neuropathol Commun. .

Abstract

Introduction: Amyloid β (Aβ) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). Aβ also deposits on the walls of arterioles as cerebral amyloid angiopathy (CAA) in most cases of AD and sometimes independently of AD. Apolipoprotein E (apoE) ɛ4 is associated with increases in both Aβ plaques and CAA in humans. Studies in mouse models that develop Aβ deposition have shown that murine apoE and human apoE4 have different abilities to facilitate plaque or CAA formation when studied independently. To better understand and compare the effects of murine apoE and human apoE4, we bred 5XFAD (line 7031) transgenic mice so that they expressed one copy of murine apoE and one copy of human apoE4 under the control of the normal murine apoE regulatory elements (5XFAD/apoE(m/4)).

Results: The 5XFAD/apoE(m/4) mice contained levels of parenchymal CAA that were intermediate between 5XFAD/apoE(m/m) and 5XFAD/apoE(4/4) mice. In 5XFAD/apoE(m/4) mice, we found that Aβ parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with Aβ in plaques versus CAA. More importantly, within the brain parenchyma of the 5XFAD/apoE(m/4) mice, plaques contained more murine apoE, which on its own results in more pronounced and earlier plaque formation, while CAA contained more human apoE4 which on its own results in more pronounced CAA formation. We further confirmed the co-aggregation of mouse apoE with Aβ in plaques by showing a strong correlation between insoluble mouse apoE and insoluble Aβ in PS1APP-21/apoE(m/4) mice which develop plaques without CAA.

Conclusions: These studies suggest that both murine apoE and human apoE4 facilitate differential opposing effects in influencing Aβ plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.

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Figures

Fig. 1
Fig. 1
ApoE4 shifted parenchymal Aβ deposition from plaques to parenchymal CAA in the 5XFAD mice. 8 ~ 10 months old 5XFAD/apoEm/m, 5XFAD/apoEm/4 and 5XFAD/apoE4/4 mice were stained with X-34. a Representative brain sections with CAA (empty arrows) and plaques (solid arrows). Scale bar, 1 mm. The right panel is the high power magnification of the area labeled in the squares in the corresponding left-side images. b The % area covered by parenchymal fibrillar plaques in the cortex. c The % area covered by parenchymal CAA quantified in the cortex (n = 3-9/group; *p < 0.05, One-way ANOVA followed by Tukey post-test)
Fig. 2
Fig. 2
Co-localization of mouse apoE and apoE4 in CAA or plaques within the same brain parenchyma in 5XFAD/apoEm/4 mice. 10-month-old 5XFAD/apoEm/4 mice were co-stained with HJ6.3-Alexa 568 for mouse apoE, HJ15.7-Alexa 488 for apoE4, and X-34 for fibrillar amyloid. a-b Representative images of co-staining for mouse apoE and apoE4 in the plaques and % area of plaque covered by different apoE. c-d Representative images of co-staining for mouse apoE and apoE4 in parenchymal CAA and % area of parenchymal CAA covered by different apoE. Values connected by lines were measured from the same animals (n = 9/group; *p < 0.05, ***p < 0.001, paired t-test)
Fig. 3
Fig. 3
Comparison between apoE co-localization in parenchymal and leptomeningeal CAA in the same 5XFAD/apoEm/4 brains. Brain sections from 10 months old 5XFAD/apoEm/4 animals were co-stained with HJ6.3-Alexa 568 for mouse apoE, HJ15.7-Alexa 488 for human apoE4, and X-34 for fibrillar amyloid. a-b Representative images of co-staining for mouse apoE and apoE4 in the leptomeningeal CAA and % area of leptomeningeal CAA covered by different apoE (n = 9/group). Scale bars, 50 μm. c % area of plaque, parenchymal and leptomeningeal CAA covered by mouse apoE. d % area of plaque, parenchymal and leptomeningeal CAA covered by human apoE4. Values connected by lines were measured from the same animals (n = 8/group; **p < 0.01, ***p < 0.001, One-way ANOVA repeated measures)
Fig. 4
Fig. 4
Co-localization of mouse apoE and apoE4 in plaques within the same brain parenchyma in APPPS1-21/apoEm/4 mice. Brain sections from 85-day-old APPPS1-21/apoEm/4 animals (n = 7) were co-stained with HJ6.3-Alexa 568 for mouse apoE, HJ15.7-Alexa 488 for human apoE4, and X-34 for fibrillar amyloid. a Representative images and the % of plaques containing both mouse apoE and apoE4 (scale bar, 20 μm). b Representative images and the % of plaques containing only mouse apoE (scale bar, 20 μm)
Fig. 5
Fig. 5
ApoE levels in 85-day-old apoEm/4 and APPPS1-21/apoEm/4 brains. The cortices were homogenized in PBS, followed by 1 % Triton X-100 and 5 M guanidine and apoE levels were measured by ELISA. a-b Absolute concentrations and fractional distribution of mouse apoE and apoE4 in apoEm/4 mice (n = 10). c-d Absolute concentrations and fractional distribution of mouse apoE and apoE4 in APPPS1-21/apoEm/4 mice (n = 10; *p < 0.05; **p < 0.01; ***p < 0.001, Two-way ANOVA for repeated measures followed by Bonferroni post-test). e-g Correlations of Aβ42 with mouse apoE, apoE4 and Aβ40 in the insoluble fraction of APPPS1-21/apoEm/4 cortices (n = 10)
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