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APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice.
Neurosci Lett. 2014 Feb 07; 560:131-6.NL

Abstract

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 (Aβ) levels, as independently both the loss of estrogen and APOE4 increases Aβ accumulation. Thus, in this study, 3-month old female EFAD mice (5XFAD mice crossed with apoE-targeted replacement mice), which express increased levels of Aβ42 and human APOE were ovariectomized and treated for 3 months with either 17-β estradiol (OVX(ET+), 0.25mg total) or vehicle control (OVX(ET-)) and the effects on Aβ accumulation were determined. Compared to the OVX(ET-) cohort, in the OVX(ET+) cohort, extracellular amyloid and Aβ 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 Aβ levels with APOE4, and decreased soluble Aβ42 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 Aβ42. However, for APOE4 carriers, the efficacy of ET will be dependent on the relative impact of extracellular and soluble Aβ on AD-induced neurodegeneration.

Authors+Show Affiliations

Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: mladu@uic.edu.Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24368217

Citation

Kunzler, Jacqueline, et al. "APOE Modulates the Effect of Estrogen Therapy On Aβ Accumulation EFAD-Tg Mice." Neuroscience Letters, vol. 560, 2014, pp. 131-6.
Kunzler J, Youmans KL, Yu C, et al. APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice. Neurosci Lett. 2014;560:131-6.
Kunzler, J., Youmans, K. L., Yu, C., Ladu, M. J., & Tai, L. M. (2014). APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice. Neuroscience Letters, 560, 131-6. https://doi.org/10.1016/j.neulet.2013.12.032
Kunzler J, et al. APOE Modulates the Effect of Estrogen Therapy On Aβ Accumulation EFAD-Tg Mice. Neurosci Lett. 2014 Feb 7;560:131-6. PubMed PMID: 24368217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice. AU - Kunzler,Jacqueline, AU - Youmans,Katherine L, AU - Yu,Chunjiang, AU - Ladu,Mary Jo, AU - Tai,Leon M, Y1 - 2013/12/22/ PY - 2013/10/27/received PY - 2013/12/11/revised PY - 2013/12/13/accepted PY - 2013/12/26/entrez PY - 2013/12/26/pubmed PY - 2014/9/10/medline KW - AD KW - AD transgenic mouse model KW - APOE KW - Alzheimer's disease KW - Amyloid-β KW - Aβ KW - ET KW - Estrogen KW - FAD KW - HRT KW - OVX KW - OVX(ET+) KW - OVX(ET−) KW - Soluble Aβ KW - Thio-S KW - amyloid-β KW - apoE KW - apolipoprotein E KW - estrogen therapy KW - familial AD KW - hormone replacement therapy KW - ovariectomy KW - ovariectomy with ET KW - ovariectomy without ET KW - thioflavin S SP - 131 EP - 6 JF - Neuroscience letters JO - Neurosci. Lett. VL - 560 N2 - 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 (Aβ) levels, as independently both the loss of estrogen and APOE4 increases Aβ accumulation. Thus, in this study, 3-month old female EFAD mice (5XFAD mice crossed with apoE-targeted replacement mice), which express increased levels of Aβ42 and human APOE were ovariectomized and treated for 3 months with either 17-β estradiol (OVX(ET+), 0.25mg total) or vehicle control (OVX(ET-)) and the effects on Aβ accumulation were determined. Compared to the OVX(ET-) cohort, in the OVX(ET+) cohort, extracellular amyloid and Aβ 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 Aβ levels with APOE4, and decreased soluble Aβ42 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 Aβ42. However, for APOE4 carriers, the efficacy of ET will be dependent on the relative impact of extracellular and soluble Aβ on AD-induced neurodegeneration. SN - 1872-7972 UR - https://www.unboundmedicine.com/medline/citation/24368217/APOE_modulates_the_effect_of_estrogen_therapy_on_Aβ_accumulation_EFAD_Tg_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(13)01113-0 DB - PRIME DP - Unbound Medicine ER -