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

作者：Liao Fan; Zhang Tony J; Jiang Hong; Lefton Katheryn B; Robinson Grace O; Vassar Robert; Sullivan Patrick M; Holtzman David M^*

来源：Acta Neuropathologica Communications, 2015, 3(1): 70.

DOI：10.1186/s40478-015-0250-y

• Alzheimer's disease
• Apolipoprotein E
• Amyloid plaques
• Cerebral amyloid angiopathy

Introduction: Amyloid beta (A beta) accumulates in the extracellular space as diffuse and neuritic plaques in Alzheimer's disease (AD). A beta 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) epsilon 4 is associated with increases in both A beta plaques and CAA in humans. Studies in mouse models that develop A beta 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 A beta parenchymal plaques co-localized with much more apoE than did parenchymal CAA, suggesting differential co-aggregation of apoE with A beta 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 A beta in plaques by showing a strong correlation between insoluble mouse apoE and insoluble A beta 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 A beta plaques versus CAA via different co-aggregation with these two amyloid lesions and set the stage for understanding these effects at a molecular level.

• 出版日期2015-11-10
• 单位西北大学