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

Dec 26, 2013Neuroscience letters

APOE influences how estrogen therapy affects amyloid buildup in Alzheimer's model mice

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Abstract

APOE4, a significant genetic risk factor for Alzheimer's disease, may influence the effects of estrogen therapy on amyloid-beta levels.

Loss of estrogen is associated with an increased risk of Alzheimer's disease in post-menopausal women.
APOE4 increases the risk for Alzheimer's disease up to 15-fold compared to APOE3 and has a greater negative impact on women.
Estrogen therapy resulted in decreased amyloid-beta accumulation in the brains of female mice with APOE2 and APOE3, but increased accumulation in those with APOE4.
Biochemical analysis showed that APOE4 carriers had increased total and insoluble amyloid-beta levels and decreased soluble amyloid-beta levels after estrogen therapy.
Estrogen therapy may benefit women without the APOE4 allele by reducing amyloid-beta levels, while its effects in APOE4 carriers could vary.

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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.

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

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