title: APOE modulates the effect of estrogen therapy on Aβ accumulation EFAD-Tg mice.
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.affiliation: Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kunzler
authors.affiliation: Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Youmans
authors.affiliation: Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: mladu@uic.edu.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Ladu
authors.affiliation: Department of Anatomy & Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use; D008822:Mice, Transgenic; D009154:Mutation; D010052:Ovariectomy; D058225:Plaque, Amyloid / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D004967:Estrogens; D004958:Estradiol
keywords: AD; AD transgenic mouse model; APOE; Alzheimer's disease; Amyloid-β; Aβ; ET; Estrogen; FAD; HRT; OVX; OVX(ET+); OVX(ET−); Soluble Aβ; Thio-S; amyloid-β; apoE; apolipoprotein E; estrogen therapy; familial AD; hormone replacement therapy; ovariectomy; ovariectomy with ET; ovariectomy without ET; thioflavin S