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

Publication ,  Journal Article
Liao, F; Zhang, TJ; Jiang, H; Lefton, KB; Robinson, GO; Vassar, R; Sullivan, PM; Holtzman, DM
Published in: Acta Neuropathol Commun
November 10, 2015

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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Published In

Acta Neuropathol Commun

DOI

EISSN

2051-5960

Publication Date

November 10, 2015

Volume

3

Start / End Page

70

Location

England

Related Subject Headings

  • Presenilin-1
  • Plaque, Amyloid
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Gene Expression Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Disease Models, Animal
 

Citation

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Liao, F., Zhang, T. J., Jiang, H., Lefton, K. B., Robinson, G. O., Vassar, R., … Holtzman, D. M. (2015). Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol Commun, 3, 70. https://doi.org/10.1186/s40478-015-0250-y
Liao, Fan, Tony J. Zhang, Hong Jiang, Katheryn B. Lefton, Grace O. Robinson, Robert Vassar, Patrick M. Sullivan, and David M. Holtzman. “Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.Acta Neuropathol Commun 3 (November 10, 2015): 70. https://doi.org/10.1186/s40478-015-0250-y.
Liao, Fan, et al. “Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.Acta Neuropathol Commun, vol. 3, Nov. 2015, p. 70. Pubmed, doi:10.1186/s40478-015-0250-y.
Liao F, Zhang TJ, Jiang H, Lefton KB, Robinson GO, Vassar R, Sullivan PM, Holtzman DM. Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models. Acta Neuropathol Commun. 2015 Nov 10;3:70.
Journal cover image

Published In

Acta Neuropathol Commun

DOI

EISSN

2051-5960

Publication Date

November 10, 2015

Volume

3

Start / End Page

70

Location

England

Related Subject Headings

  • Presenilin-1
  • Plaque, Amyloid
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Humans
  • Gene Expression Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Disease Models, Animal