APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice

NEUROSCIENCE LETTERS

卷:560

Article

Kunzler, Jacqueline¹  Youmans, Katherine L.¹  Yu, Chunjiang¹  LaDu, Mary Jo¹  Tai, Leon M.¹ 

[1] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA

关键词: Alzheimer's disease;    Estrogen;    Amyloid-beta;    APOE;    Soluble A beta;    AD transgenic mouse model;   

DOI  :  10.1016/j.neulet.2013.12.032

来源: Elsevier

【 摘 要 】

The post-menopausal loss of estrogen is key in the increased incidence of Alzheimer's disease (AD) in women. However, estrogen therapy (ET) clinical trials have produced conflicting results. The APOE gene of apolipoprotein E (apoE) likely modulates the effects of ET in AD. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared with APOE3, and the negative effect of APOE4 on AD risk and neuropathology is greater in women than men. The interactive effects of APOE and ET may converge on modulation of amyloid-beta (A beta) levels, as independently both the loss of estrogen and APOE4 increases All accumulation. Thus, in this study, 3-month old female EFAD mice (5XFAD mice crossed with apoE-targeted replacement mice), which express increased levels of Af342 and human APOE were ovariectomized and treated for 3 months with either 17-beta estradiol (OVXET+, 0.25 mg total) or vehicle control (OVXET-) and the effects on A beta accumulation were determined. Compared to the OVXET-cohort, in the OVXET+ cohort, extracellular amyloid and A beta deposition in the hippocampus and cortex were decreased with APOE2 and APOE3, but were increased with APOE4 by IHC. Biochemical analysis demonstrated increased total and insoluble A beta levels with APOE4, and decreased soluble A beta 42 levels with both APOE3 and APOE4, after ET. These data suggest that ET administered at menopause may benefit APOE4 negative women by decreasing extracellular and soluble A beta 42. However, for APOE4 carriers, the efficacy of ET will be dependent on the relative impact of extracellular and soluble A beta on AD-induced neurodegeneration. (C) 2014 Published by Elsevier Ireland Ltd.

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