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Effects of E 2 and P 4 on IDE expression levels. Representative Western blots show regulation of IDE protein levels by E 2 and P 4 treatment in 

Effects of E 2 and P 4 on IDE expression levels. Representative Western blots show regulation of IDE protein levels by E 2 and P 4 treatment in 

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The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) an...

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... ϩ E 2 ϩ P4 cont ) but not by cyclic P 4 (OVX ϩ E 2 ϩ P4 cyc ) ( Fig 5, A and B). There were also significant treatment effects on mRNA levels of ACE [F (6,21) ϭ 10.9, P Ͻ 0.001]. In comparison with the Sham group, OVX was associated with a significant increase in ACE mRNA that was significantly attenuated in the OVX ϩ E 2 group. Cyclic P 4 (OVX ϩ P cyc ) did not significantly reduce ACE mRNA, but continuous P 4 (OVX ϩ P4 cont ) had an intermediate effect yielding ACE mRNA levels that were not significantly different from either Sham OVX or OVX (Fig. 5, A and C). Both P 4 treatments significantly inhibited the effect of E 2 on ACE mRNA (Fig. 5, A and C). There was no statistically significant main effect of treatment group on ECE2 mRNA levels [F (6,14) ϭ 1.5, P ϭ 0.24] (Fig. 5, A and D). Levels of TTR mRNA levels significantly differed across groups [F (6,21) ϭ 5.5, P Ͻ 0.01]. Although there were no significant effects of OVX or E 2 treatment, there was a modest increase in TTR mRNA in the OVX ϩ P4 cyc group relative to both Sham and OVX groups (Fig. 5, A and E). The only A ␤ clearance factor that was positively regulated at the mRNA level by E 2 and/or P 4 across all of our cell culture and in vivo paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically significant effects apparent at 0.1 n M (Fig. 6, A and F) [F (5,12) ϭ 92.6, P Ͻ 0.001]. In cultures treated with 10 n M E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) ϭ 142.1, P Ͻ 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects observed between concentrations of 0.3 n M and 300 n M [F ϭ 33.4, P Ͻ 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) ϭ 23.9, P Ͻ 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) ϭ 20.4, P Ͻ 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVX ϩ E 2 ) or P 4 (OVX ϩ P 4 ) yielded significant increases in IDE protein levels, with the OVX ϩ E 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and J). The significant positive regulation of the A ␤ degrading enzyme IDE by both E 2 and P 4 across culture and in vivo paradigms suggests a possible role in regulating brain levels of A ␤ . To begin investigating this possibility, we ho- mogenized one hemi-brain from each of the rats in the extended hormone treatment experiment to analyze soluble A ␤ levels by ELISA. Our results indicate a statistically significant effect of treatment on A ␤ 42 levels [F (3,28) ϭ 3.3, P ϭ 0.01]. Ovarian hormone depletion associated with OVX resulted in a significant, approximately 2-fold increase in A ␤ that was largely prevented by continuous E 2 treatment (OVX ϩ E 2 ) (Fig. 7). Treatment with P 4 alone delivered either continuously (OVX ϩ P4 cont ) or cyclically (OVX ϩ P4 cyc ) did not significantly lower A ␤ levels relative to the OVX group. Interestingly, the regimen of cyclic P 4 in combination with E 2 (OVX ϩ E2 ϩ P4 cyc ) showed the lowest A ␤ 42 levels. Although there are no definitive approaches for preventing and treating AD, clinical studies have demonstrated that the risk of AD in women can be significantly reduced by hormone therapy. Because accumulation of A ␤ is widely theo- rized to initiate AD pathogenesis (51), optimizing hormone therapy will likely require thorough understanding of how estrogens and progestagens regulate A ␤ accumulation. Prior work has clearly linked E 2 with regulation of A ␤ production by affecting APP metabolism and trafficking (52). Recent work has demonstrated that E 2 and P 4 may also play a role in A ␤ clearance (2). Our results suggest that E 2 and P 4 are able to affect mRNA expression of some but not all A ␤ clearance factors. Most notably, data in neuron cultures show that E 2 affects IDE, ACE, and ECE2 mRNA in dose- and time-dependent manners whereas P 4 regulates the expression levels of IDE, ACE, and TTR mRNA. In rat brain, both E 2 and P 4 are also shown to regulate IDE expression. Importantly, we also assess the relationship of expression changes with endogenous soluble brain levels of A ␤ , demonstrating an inverse association between the levels of IDE and soluble A ␤ . Our data demonstrate that E 2 regulates expression of several factors involved in A ␤ clearance. The most robust effect across paradigms was the E 2 -induced increase in IDE expression, which was observed at both the mRNA and protein levels. The data show that the approximately 2-fold increase in IDE mRNA is ER dependent because it is blocked by an ER antagonist but mimicked by agonists for both ER ␣ and ER ␤ . This observation is consistent with the finding that uterine IDE level and activity decrease during low E 2 phase and increase during high E 2 phase of the estrous cycle (53). In addition, a recent independent term and extended P4 exposure in vivo , IDE mRNA con- tinued to exhibit strong up-regulation by P 4 but TTR mRNA was only modestly increased and ACE expression was not significantly affected. This incomplete concor- dance in findings between in vitro and in vivo paradigms suggests that although P 4 and E 2 have the potential to regulate numerous genes in simple culture systems, only a subset of these effects are manifested at significant levels in vivo owing to the influence of multiple tissue-specific and systems-wide interactions. The lack of significant P 4 regulation of ACE mRNA in vivo is consistent with a prior mulation in 3xTg-AD mice, whereas continuous P 4 but not cyclic P 4 prevented the A ␤ -lowering action of E 2 (22). The differential effects of continuous vs. cyclic P 4 may reflect broad differences in gene expression profiles that vary according to hormone regimens (76). Unclear is whether delivery of E 2 in a cyclic manner may offer further benefits, although the near-maximal effects of the used continuous E 2 delivery relative to OVX alone suggests limited opportunity for improvement. The mechanism underlying the regulation of A ␤ -degrading enzymes by E 2 and P 4 is not well defined. Some evidence suggests roles of the estrogen receptors ER ␣ and ER ␤ in E 2 -mediated changes (54, 65, 67). We show that the E 2 regulation of IDE mRNA is blocked by the antiestrogen ICI 182,780, implicating ER-dependent signaling. We further demonstrate that both ER ␣ and ER ␤ may be important in the E 2 -mediated regulation of IDE because both ER ␣ and ER ␤ agonists up-regulated IDE transcript expression in a dose-dependent manner. E 2 could directly increase the IDE mRNA expression via classic genomic signaling in which ER bind to estrogen-response elements (ERE) on the target gene for transcriptional regulation. Consistent with this possibility, analysis of the promoter region of rat IDE gene using MatInspector (77) reveals four putative canonical ERE (GGTCAnnnTGACC). Al- ternatively, E 2 may increase IDE expression indirectly via activation of one or more of the cell-signaling pathways. For example, E 2 is known to activate phosphatidylinosi- tol-3 kinase (78), which in turn is implicated in the insulin- dependent up-regulation of IDE (79). The role of PR in regulating IDE is unclear. Although the PR antagonists RU486 and Org 31710 inhibited P 4 regulation of TTR mRNA, the antagonists failed to block the P 4 -mediated increase in IDE mRNA levels in neuron culture, suggesting that neither of the two PR isoforms A and B mediates this P 4 response. Future work will determine whether the mechanism involves a nonclassical mediator of P 4 action ( e.g. PR membrane component 1) or perhaps P 4 metabolites ( e.g. allopregnanolone). Further investigation of the roles of ER and PR is required to completely understand the mechanism underlying the observed regulation of these A ␤ clearance factors. Our study provides novel insight into the roles of individual and interactive effects of E 2 and P 4 in regulating A ␤ by analyzing their effects on the expression of A ␤ clearance factors. The most significant observation is that both E 2 and P 4 increase IDE mRNA expression in vitro and in vivo . This, taken together with the inverse relationship in vivo between IDE expression and A ␤ levels, suggests an- other possible mechanism by which E 2 and P 4 can affect A ␤ accumulation. Continued investigation of the interactions between E and P in regulating A ␤ production and degradation is essential for optimizing hormone-based strategies for the prevention and/or treatment of ...
Context 2
... ϩ E 2 ϩ P4 cont ) but not by cyclic P 4 (OVX ϩ E 2 ϩ P4 cyc ) ( Fig 5, A and B). There were also significant treatment effects on mRNA levels of ACE [F (6,21) ϭ 10.9, P Ͻ 0.001]. In comparison with the Sham group, OVX was associated with a significant increase in ACE mRNA that was significantly attenuated in the OVX ϩ E 2 group. Cyclic P 4 (OVX ϩ P cyc ) did not significantly reduce ACE mRNA, but continuous P 4 (OVX ϩ P4 cont ) had an intermediate effect yielding ACE mRNA levels that were not significantly different from either Sham OVX or OVX (Fig. 5, A and C). Both P 4 treatments significantly inhibited the effect of E 2 on ACE mRNA (Fig. 5, A and C). There was no statistically significant main effect of treatment group on ECE2 mRNA levels [F (6,14) ϭ 1.5, P ϭ 0.24] (Fig. 5, A and D). Levels of TTR mRNA levels significantly differed across groups [F (6,21) ϭ 5.5, P Ͻ 0.01]. Although there were no significant effects of OVX or E 2 treatment, there was a modest increase in TTR mRNA in the OVX ϩ P4 cyc group relative to both Sham and OVX groups (Fig. 5, A and E). The only A ␤ clearance factor that was positively regulated at the mRNA level by E 2 and/or P 4 across all of our cell culture and in vivo paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically significant effects apparent at 0.1 n M (Fig. 6, A and F) [F (5,12) ϭ 92.6, P Ͻ 0.001]. In cultures treated with 10 n M E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) ϭ 142.1, P Ͻ 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects observed between concentrations of 0.3 n M and 300 n M [F ϭ 33.4, P Ͻ 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) ϭ 23.9, P Ͻ 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) ϭ 20.4, P Ͻ 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVX ϩ E 2 ) or P 4 (OVX ϩ P 4 ) yielded significant increases in IDE protein levels, with the OVX ϩ E 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and J). The significant positive regulation of the A ␤ degrading enzyme IDE by both E 2 and P 4 across culture and in vivo paradigms suggests a possible role in regulating brain levels of A ␤ . To begin investigating this possibility, we ho- mogenized one hemi-brain from each of the rats in the extended hormone treatment experiment to analyze soluble A ␤ levels by ELISA. Our results indicate a statistically significant effect of treatment on A ␤ 42 levels [F (3,28) ϭ 3.3, P ϭ 0.01]. Ovarian hormone depletion associated with OVX resulted in a significant, approximately 2-fold increase in A ␤ that was largely prevented by continuous E 2 treatment (OVX ϩ E 2 ) (Fig. 7). Treatment with P 4 alone delivered either continuously (OVX ϩ P4 cont ) or cyclically (OVX ϩ P4 cyc ) did not significantly lower A ␤ levels relative to the OVX group. Interestingly, the regimen of cyclic P 4 in combination with E 2 (OVX ϩ E2 ϩ P4 cyc ) showed the lowest A ␤ 42 levels. Although there are no definitive approaches for preventing and treating AD, clinical studies have demonstrated that the risk of AD in women can be significantly reduced by hormone therapy. Because accumulation of A ␤ is widely theo- rized to initiate AD pathogenesis (51), optimizing hormone therapy will likely require thorough understanding of how estrogens and progestagens regulate A ␤ accumulation. Prior work has clearly linked E 2 with regulation of A ␤ production by affecting APP metabolism and trafficking (52). Recent work has demonstrated that E 2 and P 4 may also play a role in A ␤ clearance (2). Our results suggest that E 2 and P 4 are able to affect mRNA expression of some but not all A ␤ clearance factors. Most notably, data in neuron cultures show that E 2 affects IDE, ACE, and ECE2 mRNA in dose- and time-dependent manners whereas P 4 regulates the expression levels of IDE, ACE, and TTR mRNA. In rat brain, both E 2 and P 4 are also shown to regulate IDE expression. Importantly, we also assess the relationship of expression changes with endogenous soluble brain levels of A ␤ , demonstrating an inverse association between the levels of IDE and soluble A ␤ . Our data demonstrate that E 2 regulates expression of several factors involved in A ␤ clearance. The most robust effect across paradigms was the E 2 -induced increase in IDE expression, which was observed at both the mRNA and protein levels. The data show that the approximately 2-fold increase in IDE mRNA is ER dependent because it is blocked by an ER antagonist but mimicked by agonists for both ER ␣ and ER ␤ . This observation is consistent with the finding that uterine IDE level and activity decrease during low E 2 phase and increase during high E 2 phase of the estrous cycle (53). In addition, a recent independent term and extended P4 exposure in vivo , IDE mRNA con- tinued to exhibit strong up-regulation by P 4 but TTR mRNA was only modestly increased and ACE expression was not significantly affected. This incomplete concor- dance in findings between in vitro and in vivo paradigms suggests that although P 4 and E 2 have the potential to regulate numerous genes in simple culture systems, only a subset of these effects are manifested at significant levels in vivo owing to the influence of multiple tissue-specific and systems-wide interactions. The lack of significant P 4 regulation of ACE mRNA in vivo is consistent with a prior mulation in 3xTg-AD mice, whereas continuous P 4 but not cyclic P 4 prevented the A ␤ -lowering action of E 2 (22). The differential effects of continuous vs. cyclic P 4 may reflect broad differences in gene expression profiles that vary according to hormone regimens (76). Unclear is whether delivery of E 2 in a cyclic manner may offer further benefits, although the near-maximal effects of the used continuous E 2 delivery relative to OVX alone suggests limited opportunity for improvement. The mechanism underlying the regulation of A ␤ -degrading enzymes by E 2 and P 4 is not well defined. Some evidence suggests roles of the estrogen receptors ER ␣ and ER ␤ in E 2 -mediated changes (54, 65, 67). We show that the E 2 regulation of IDE mRNA is blocked by the antiestrogen ICI 182,780, implicating ER-dependent signaling. We further demonstrate that both ER ␣ and ER ␤ may be important in the E 2 -mediated regulation of IDE because both ER ␣ and ER ␤ agonists up-regulated IDE transcript expression in a dose-dependent manner. E 2 could directly increase the IDE mRNA expression via classic genomic signaling in which ER bind to estrogen-response elements (ERE) on the target gene for transcriptional regulation. Consistent with this possibility, analysis of the promoter region of rat IDE gene using MatInspector (77) reveals four putative canonical ERE (GGTCAnnnTGACC). Al- ternatively, E 2 may increase IDE expression indirectly via activation of one or more of the cell-signaling pathways. For example, E 2 is known to activate phosphatidylinosi- tol-3 kinase (78), which in turn is implicated in the insulin- dependent up-regulation of IDE (79). The role of PR in regulating IDE is unclear. Although the PR antagonists RU486 and Org 31710 inhibited P 4 regulation of TTR mRNA, the antagonists failed to block the P 4 -mediated increase in IDE mRNA levels in neuron culture, suggesting that neither of the two PR isoforms A and B mediates this P 4 response. Future work will determine whether the mechanism involves a nonclassical mediator of P 4 action ( e.g. PR membrane component 1) or perhaps P 4 metabolites ( e.g. allopregnanolone). Further investigation of the roles of ER and PR is required to completely understand the mechanism underlying the observed regulation of these A ␤ clearance factors. Our study provides novel insight into the roles of individual and interactive effects of E 2 and P 4 in regulating A ␤ by analyzing their effects on the expression of A ␤ clearance factors. The most significant observation is that both E 2 and P 4 increase IDE mRNA expression in vitro and in vivo . This, taken together with the inverse relationship in vivo between IDE expression and A ␤ levels, suggests an- other possible mechanism by which E 2 and P 4 can affect A ␤ accumulation. Continued investigation of the interactions between E and P in regulating A ␤ production and degradation is essential for optimizing hormone-based strategies for the prevention and/or treatment of ...
Context 3
... ϩ E 2 ϩ P4 cont ) but not by cyclic P 4 (OVX ϩ E 2 ϩ P4 cyc ) ( Fig 5, A and B). There were also significant treatment effects on mRNA levels of ACE [F (6,21) ϭ 10.9, P Ͻ 0.001]. In comparison with the Sham group, OVX was associated with a significant increase in ACE mRNA that was significantly attenuated in the OVX ϩ E 2 group. Cyclic P 4 (OVX ϩ P cyc ) did not significantly reduce ACE mRNA, but continuous P 4 (OVX ϩ P4 cont ) had an intermediate effect yielding ACE mRNA levels that were not significantly different from either Sham OVX or OVX (Fig. 5, A and C). Both P 4 treatments significantly inhibited the effect of E 2 on ACE mRNA (Fig. 5, A and C). There was no statistically significant main effect of treatment group on ECE2 mRNA levels [F (6,14) ϭ 1.5, P ϭ 0.24] (Fig. 5, A and D). Levels of TTR mRNA levels significantly differed across groups [F (6,21) ϭ 5.5, P Ͻ 0.01]. Although there were no significant effects of OVX or E 2 treatment, there was a modest increase in TTR mRNA in the OVX ϩ P4 cyc group relative to both Sham and OVX groups (Fig. 5, A and E). The only A ␤ clearance factor that was positively regulated at the mRNA level by E 2 and/or P 4 across all of our cell culture and in vivo paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically significant effects apparent at 0.1 n M (Fig. 6, A and F) [F (5,12) ϭ 92.6, P Ͻ 0.001]. In cultures treated with 10 n M E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) ϭ 142.1, P Ͻ 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects observed between concentrations of 0.3 n M and 300 n M [F ϭ 33.4, P Ͻ 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) ϭ 23.9, P Ͻ 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) ϭ 20.4, P Ͻ 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVX ϩ E 2 ) or P 4 (OVX ϩ P 4 ) yielded significant increases in IDE protein levels, with the OVX ϩ E 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and J). The significant positive regulation of the A ␤ degrading enzyme IDE by both E 2 and P 4 across culture and in vivo paradigms suggests a possible role in regulating brain levels of A ␤ . To begin investigating this possibility, we ho- mogenized one hemi-brain from each of the rats in the extended hormone treatment experiment to analyze soluble A ␤ levels by ELISA. Our results indicate a statistically significant effect of treatment on A ␤ 42 levels [F (3,28) ϭ 3.3, P ϭ 0.01]. Ovarian hormone depletion associated with OVX resulted in a significant, approximately 2-fold increase in A ␤ that was largely prevented by continuous E 2 treatment (OVX ϩ E 2 ) (Fig. 7). Treatment with P 4 alone delivered either continuously (OVX ϩ P4 cont ) or cyclically (OVX ϩ P4 cyc ) did not significantly lower A ␤ levels relative to the OVX group. Interestingly, the regimen of cyclic P 4 in combination with E 2 (OVX ϩ E2 ϩ P4 cyc ) showed the lowest A ␤ 42 levels. Although there are no definitive approaches for preventing and treating AD, clinical studies have demonstrated that the risk of AD in women can be significantly reduced by hormone therapy. Because accumulation of A ␤ is widely theo- rized to initiate AD pathogenesis (51), optimizing hormone therapy will likely require thorough understanding of how estrogens and progestagens regulate A ␤ accumulation. Prior work has clearly linked E 2 with regulation of A ␤ production by affecting APP metabolism and trafficking (52). Recent work has demonstrated that E 2 and P 4 may also play a role in A ␤ clearance (2). Our results suggest that E 2 and P 4 are able to affect mRNA expression of some but not all A ␤ clearance factors. Most notably, data in neuron cultures show that E 2 affects IDE, ACE, and ECE2 mRNA in dose- and time-dependent manners whereas P 4 regulates the expression levels of IDE, ACE, and TTR mRNA. In rat brain, both E 2 and P 4 are also shown to regulate IDE expression. Importantly, we also assess the relationship of expression changes with endogenous soluble brain levels of A ␤ , demonstrating an inverse association between the levels of IDE and soluble A ␤ . Our data demonstrate that E 2 regulates expression of several factors involved in A ␤ clearance. The most robust effect across paradigms was the E 2 -induced increase in IDE expression, which was observed at both the mRNA and protein levels. The data show that the approximately 2-fold increase in IDE mRNA is ER dependent because it is blocked by an ER antagonist but mimicked by agonists for both ER ␣ and ER ␤ . This observation is consistent with the finding that uterine IDE level and activity decrease during low E 2 phase and increase during high E 2 phase of the estrous cycle (53). In addition, a recent independent term and extended P4 exposure in vivo , IDE mRNA con- tinued to exhibit strong up-regulation by P 4 but TTR mRNA was only modestly increased and ACE expression was not significantly affected. This incomplete concor- dance in findings between in vitro and in vivo paradigms suggests that although P 4 and E 2 have the potential to regulate numerous genes in simple culture systems, only a subset of these effects are manifested at significant levels in vivo owing to the influence of multiple tissue-specific and systems-wide interactions. The lack of significant P 4 regulation of ACE mRNA in vivo is consistent with a prior mulation in 3xTg-AD mice, whereas continuous P 4 but not cyclic P 4 prevented the A ␤ -lowering action of E 2 (22). The differential effects of continuous vs. cyclic P 4 may reflect broad differences in gene expression profiles that vary according to hormone regimens (76). Unclear is whether delivery of E 2 in a cyclic manner may offer further benefits, although the near-maximal effects of the used continuous E 2 delivery relative to OVX alone suggests limited opportunity for improvement. The mechanism underlying the regulation of A ␤ -degrading enzymes by E 2 and P 4 is not well defined. Some evidence suggests roles of the estrogen receptors ER ␣ and ER ␤ in E 2 -mediated changes (54, 65, 67). We show that the E 2 regulation of IDE mRNA is blocked by the antiestrogen ICI 182,780, implicating ER-dependent signaling. We further demonstrate that both ER ␣ and ER ␤ may be important in the E 2 -mediated regulation of IDE because both ER ␣ and ER ␤ agonists up-regulated IDE transcript expression in a dose-dependent manner. E 2 could directly increase the IDE mRNA expression via classic genomic signaling in which ER bind to estrogen-response elements (ERE) on the target gene for transcriptional regulation. Consistent with this possibility, analysis of the promoter region of rat IDE gene using MatInspector (77) reveals four putative canonical ERE (GGTCAnnnTGACC). Al- ternatively, E 2 may increase IDE expression indirectly via activation of one or more of the cell-signaling pathways. For example, E 2 is known to activate phosphatidylinosi- tol-3 kinase (78), which in turn is implicated in the insulin- dependent up-regulation of IDE (79). The role of PR in regulating IDE is unclear. Although the PR antagonists RU486 and Org 31710 inhibited P 4 regulation of TTR mRNA, the antagonists failed to block the P 4 -mediated increase in IDE mRNA levels in neuron culture, suggesting that neither of the two PR isoforms A and B mediates this P 4 response. Future work will determine whether the mechanism involves a nonclassical mediator of P 4 action ( e.g. PR membrane component 1) or perhaps P 4 metabolites ( e.g. allopregnanolone). Further investigation of the roles of ER and PR is required to completely understand the mechanism underlying the observed regulation of these A ␤ clearance factors. Our study provides novel insight into the roles of individual and interactive effects of E 2 and P 4 in regulating A ␤ by analyzing their effects on the expression of A ␤ clearance factors. The most significant observation is that both E 2 and P 4 increase IDE mRNA expression in vitro and in vivo . This, taken together with the inverse relationship in vivo between IDE expression and A ␤ levels, suggests an- other possible mechanism by which E 2 and P 4 can affect A ␤ accumulation. Continued investigation of the interactions between E and P in regulating A ␤ production and degradation is essential for optimizing hormone-based strategies for the prevention and/or treatment of ...
Context 4
... ϩ E 2 ϩ P4 cont ) but not by cyclic P 4 (OVX ϩ E 2 ϩ P4 cyc ) ( Fig 5, A and B). There were also significant treatment effects on mRNA levels of ACE [F (6,21) ϭ 10.9, P Ͻ 0.001]. In comparison with the Sham group, OVX was associated with a significant increase in ACE mRNA that was significantly attenuated in the OVX ϩ E 2 group. Cyclic P 4 (OVX ϩ P cyc ) did not significantly reduce ACE mRNA, but continuous P 4 (OVX ϩ P4 cont ) had an intermediate effect yielding ACE mRNA levels that were not significantly different from either Sham OVX or OVX (Fig. 5, A and C). Both P 4 treatments significantly inhibited the effect of E 2 on ACE mRNA (Fig. 5, A and C). There was no statistically significant main effect of treatment group on ECE2 mRNA levels [F (6,14) ϭ 1.5, P ϭ 0.24] (Fig. 5, A and D). Levels of TTR mRNA levels significantly differed across groups [F (6,21) ϭ 5.5, P Ͻ 0.01]. Although there were no significant effects of OVX or E 2 treatment, there was a modest increase in TTR mRNA in the OVX ϩ P4 cyc group relative to both Sham and OVX groups (Fig. 5, A and E). The only A ␤ clearance factor that was positively regulated at the mRNA level by E 2 and/or P 4 across all of our cell culture and in vivo paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically significant effects apparent at 0.1 n M (Fig. 6, A and F) [F (5,12) ϭ 92.6, P Ͻ 0.001]. In cultures treated with 10 n M E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) ϭ 142.1, P Ͻ 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects observed between concentrations of 0.3 n M and 300 n M [F ϭ 33.4, P Ͻ 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) ϭ 23.9, P Ͻ 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) ϭ 20.4, P Ͻ 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVX ϩ E 2 ) or P 4 (OVX ϩ P 4 ) yielded significant increases in IDE protein levels, with the OVX ϩ E 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and J). The significant positive regulation of the A ␤ degrading enzyme IDE by both E 2 and P 4 across culture and in vivo paradigms suggests a possible role in regulating brain levels of A ␤ . To begin investigating this possibility, we ho- mogenized one hemi-brain from each of the rats in the extended hormone treatment experiment to analyze soluble A ␤ levels by ELISA. Our results indicate a statistically significant effect of treatment on A ␤ 42 levels [F (3,28) ϭ 3.3, P ϭ 0.01]. Ovarian hormone depletion associated with OVX resulted in a significant, approximately 2-fold increase in A ␤ that was largely prevented by continuous E 2 treatment (OVX ϩ E 2 ) (Fig. 7). Treatment with P 4 alone delivered either continuously (OVX ϩ P4 cont ) or cyclically (OVX ϩ P4 cyc ) did not significantly lower A ␤ levels relative to the OVX group. Interestingly, the regimen of cyclic P 4 in combination with E 2 (OVX ϩ E2 ϩ P4 cyc ) showed the lowest A ␤ 42 levels. Although there are no definitive approaches for preventing and treating AD, clinical studies have demonstrated that the risk of AD in women can be significantly reduced by hormone therapy. Because accumulation of A ␤ is widely theo- rized to initiate AD pathogenesis (51), optimizing hormone therapy will likely require thorough understanding of how estrogens and progestagens regulate A ␤ accumulation. Prior work has clearly linked E 2 with regulation of A ␤ production by affecting APP metabolism and trafficking (52). Recent work has demonstrated that E 2 and P 4 may also play a role in A ␤ clearance (2). Our results suggest that E 2 and P 4 are able to affect mRNA expression of some but not all A ␤ clearance factors. Most notably, data in neuron cultures show that E 2 affects IDE, ACE, and ECE2 mRNA in dose- and time-dependent manners whereas P 4 regulates the expression levels of IDE, ACE, and TTR mRNA. In rat brain, both E 2 and P 4 are also shown to regulate IDE expression. Importantly, we also assess the relationship of expression changes with endogenous soluble brain levels of A ␤ , demonstrating an inverse association between the levels of IDE and soluble A ␤ . Our data demonstrate that E 2 regulates expression of several factors involved in A ␤ clearance. The most robust effect across paradigms was the E 2 -induced increase in IDE expression, which was observed at both the mRNA and protein levels. The data show that the approximately 2-fold increase in IDE mRNA is ER dependent because it is blocked by an ER antagonist but mimicked by agonists for both ER ␣ and ER ␤ . This observation is consistent with the finding that uterine IDE level and activity decrease during low E 2 phase and increase during high E 2 phase of the estrous cycle (53). In addition, a recent independent term and extended P4 exposure in vivo , IDE mRNA con- tinued to exhibit strong up-regulation by P 4 but TTR mRNA was only modestly increased and ACE expression was not significantly affected. This incomplete concor- dance in findings between in vitro and in vivo paradigms suggests that although P 4 and E 2 have the potential to regulate numerous genes in simple culture systems, only a subset of these effects are manifested at significant levels in vivo owing to the influence of multiple tissue-specific and systems-wide interactions. The lack of significant P 4 regulation of ACE mRNA in vivo is consistent with a prior mulation in 3xTg-AD mice, whereas continuous P 4 but not cyclic P 4 prevented the A ␤ -lowering action of E 2 (22). The differential effects of continuous vs. cyclic P 4 may reflect broad differences in gene expression profiles that vary according to hormone regimens (76). Unclear is whether delivery of E 2 in a cyclic manner may offer further benefits, although the near-maximal effects of the used continuous E 2 delivery relative to OVX alone suggests limited opportunity for improvement. The mechanism underlying the regulation of A ␤ -degrading enzymes by E 2 and P 4 is not well defined. Some evidence suggests roles of the estrogen receptors ER ␣ and ER ␤ in E 2 -mediated changes (54, 65, 67). We show that the E 2 regulation of IDE mRNA is blocked by the antiestrogen ICI 182,780, implicating ER-dependent signaling. We further demonstrate that both ER ␣ and ER ␤ may be important in the E 2 -mediated regulation of IDE because both ER ␣ and ER ␤ agonists up-regulated IDE transcript expression in a dose-dependent manner. E 2 could directly increase the IDE mRNA expression via classic genomic signaling in which ER bind to estrogen-response elements (ERE) on the target gene for transcriptional regulation. Consistent with this possibility, analysis of the promoter region of rat IDE gene using MatInspector (77) reveals four putative canonical ERE (GGTCAnnnTGACC). Al- ternatively, E 2 may increase IDE expression indirectly via activation of one or more of the cell-signaling pathways. For example, E 2 is known to activate phosphatidylinosi- tol-3 kinase (78), which in turn is implicated in the insulin- dependent up-regulation of IDE (79). The role of PR in regulating IDE is unclear. Although the PR antagonists RU486 and Org 31710 inhibited P 4 regulation of TTR mRNA, the antagonists failed to block the P 4 -mediated increase in IDE mRNA levels in neuron culture, suggesting that neither of the two PR isoforms A and B mediates this P 4 response. Future work will determine whether the mechanism involves a nonclassical mediator of P 4 action ( e.g. PR membrane component 1) or perhaps P 4 metabolites ( e.g. allopregnanolone). Further investigation of the roles of ER and PR is required to completely understand the mechanism underlying the observed regulation of these A ␤ clearance factors. Our study provides novel insight into the roles of individual and interactive effects of E 2 and P 4 in regulating A ␤ by analyzing their effects on the expression of A ␤ clearance factors. The most significant observation is that both E 2 and P 4 increase IDE mRNA expression in vitro and in vivo . This, taken together with the inverse relationship in vivo between IDE expression and A ␤ levels, suggests an- other possible mechanism by which E 2 and P 4 can affect A ␤ accumulation. Continued investigation of the interactions between E and P in regulating A ␤ production and degradation is essential for optimizing hormone-based strategies for the prevention and/or treatment of ...
Context 5
... ϩ E 2 ϩ P4 cont ) but not by cyclic P 4 (OVX ϩ E 2 ϩ P4 cyc ) ( Fig 5, A and B). There were also significant treatment effects on mRNA levels of ACE [F (6,21) ϭ 10.9, P Ͻ 0.001]. In comparison with the Sham group, OVX was associated with a significant increase in ACE mRNA that was significantly attenuated in the OVX ϩ E 2 group. Cyclic P 4 (OVX ϩ P cyc ) did not significantly reduce ACE mRNA, but continuous P 4 (OVX ϩ P4 cont ) had an intermediate effect yielding ACE mRNA levels that were not significantly different from either Sham OVX or OVX (Fig. 5, A and C). Both P 4 treatments significantly inhibited the effect of E 2 on ACE mRNA (Fig. 5, A and C). There was no statistically significant main effect of treatment group on ECE2 mRNA levels [F (6,14) ϭ 1.5, P ϭ 0.24] (Fig. 5, A and D). Levels of TTR mRNA levels significantly differed across groups [F (6,21) ϭ 5.5, P Ͻ 0.01]. Although there were no significant effects of OVX or E 2 treatment, there was a modest increase in TTR mRNA in the OVX ϩ P4 cyc group relative to both Sham and OVX groups (Fig. 5, A and E). The only A ␤ clearance factor that was positively regulated at the mRNA level by E 2 and/or P 4 across all of our cell culture and in vivo paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically significant effects apparent at 0.1 n M (Fig. 6, A and F) [F (5,12) ϭ 92.6, P Ͻ 0.001]. In cultures treated with 10 n M E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) ϭ 142.1, P Ͻ 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects observed between concentrations of 0.3 n M and 300 n M [F ϭ 33.4, P Ͻ 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) ϭ 23.9, P Ͻ 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) ϭ 20.4, P Ͻ 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVX ϩ E 2 ) or P 4 (OVX ϩ P 4 ) yielded significant increases in IDE protein levels, with the OVX ϩ E 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and J). The significant positive regulation of the A ␤ degrading enzyme IDE by both E 2 and P 4 across culture and in vivo paradigms suggests a possible role in regulating brain levels of A ␤ . To begin investigating this possibility, we ho- mogenized one hemi-brain from each of the rats in the extended hormone treatment experiment to analyze soluble A ␤ levels by ELISA. Our results indicate a statistically significant effect of treatment on A ␤ 42 levels [F (3,28) ϭ 3.3, P ϭ 0.01]. Ovarian hormone depletion associated with OVX resulted in a significant, approximately 2-fold increase in A ␤ that was largely prevented by continuous E 2 treatment (OVX ϩ E 2 ) (Fig. 7). Treatment with P 4 alone delivered either continuously (OVX ϩ P4 cont ) or cyclically (OVX ϩ P4 cyc ) did not significantly lower A ␤ levels relative to the OVX group. Interestingly, the regimen of cyclic P 4 in combination with E 2 (OVX ϩ E2 ϩ P4 cyc ) showed the lowest A ␤ 42 levels. Although there are no definitive approaches for preventing and treating AD, clinical studies have demonstrated that the risk of AD in women can be significantly reduced by hormone therapy. Because accumulation of A ␤ is widely theo- rized to initiate AD pathogenesis (51), optimizing hormone therapy will likely require thorough understanding of how estrogens and progestagens regulate A ␤ accumulation. Prior work has clearly linked E 2 with regulation of A ␤ production by affecting APP metabolism and trafficking (52). Recent work has demonstrated that E 2 and P 4 may also play a role in A ␤ clearance (2). Our results suggest that E 2 and P 4 are able to affect mRNA expression of some but not all A ␤ clearance factors. Most notably, data in neuron cultures show that E 2 affects IDE, ACE, and ECE2 mRNA in dose- and time-dependent manners whereas P 4 regulates the expression levels of IDE, ACE, and TTR mRNA. In rat brain, both E 2 and P 4 are also shown to regulate IDE expression. Importantly, we also assess the relationship of expression changes with endogenous soluble brain levels of A ␤ , demonstrating an inverse association between the levels of IDE and soluble A ␤ . Our data demonstrate that E 2 regulates expression of several factors involved in A ␤ clearance. The most robust effect across paradigms was the E 2 -induced increase in IDE expression, which was observed at both the mRNA and protein levels. The data show that the approximately 2-fold increase in IDE mRNA is ER dependent because it is blocked by an ER antagonist but mimicked by agonists for both ER ␣ and ER ␤ . This observation is consistent with the finding that uterine IDE level and activity decrease during low E 2 phase and increase during high E 2 phase of the estrous cycle (53). In addition, a recent independent term and extended P4 exposure in vivo , IDE mRNA con- tinued to exhibit strong up-regulation by P 4 but TTR mRNA was only modestly increased and ACE expression was not significantly affected. This incomplete concor- dance in findings between in vitro and in vivo paradigms suggests that although P 4 and E 2 have the potential to regulate numerous genes in simple culture systems, only a subset of these effects are manifested at significant levels in vivo owing to the influence of multiple tissue-specific and systems-wide interactions. The lack of significant P 4 regulation of ACE mRNA in vivo is consistent with a prior mulation in 3xTg-AD mice, whereas continuous P 4 but not cyclic P 4 prevented the A ␤ -lowering action of E 2 (22). The differential effects of continuous vs. cyclic P 4 may reflect broad differences in gene expression profiles that vary according to hormone regimens (76). Unclear is whether delivery of E 2 in a cyclic manner may offer further benefits, although the near-maximal effects of the used continuous E 2 delivery relative to OVX alone suggests limited opportunity for improvement. The mechanism underlying the regulation of A ␤ -degrading enzymes by E 2 and P 4 is not well defined. Some evidence suggests roles of the estrogen receptors ER ␣ and ER ␤ in E 2 -mediated changes (54, 65, 67). We show that the E 2 regulation of IDE mRNA is blocked by the antiestrogen ICI 182,780, implicating ER-dependent signaling. We further demonstrate that both ER ␣ and ER ␤ may be important in the E 2 -mediated regulation of IDE because both ER ␣ and ER ␤ agonists up-regulated IDE transcript expression in a dose-dependent manner. E 2 could directly increase the IDE mRNA expression via classic genomic signaling in which ER bind to estrogen-response elements (ERE) on the target gene for transcriptional regulation. Consistent with this possibility, analysis of the promoter region of rat IDE gene using MatInspector (77) reveals four putative canonical ERE (GGTCAnnnTGACC). Al- ternatively, E 2 may increase IDE expression indirectly via activation of one or more of the cell-signaling pathways. For example, E 2 is known to activate phosphatidylinosi- tol-3 kinase (78), which in turn is implicated in the insulin- dependent up-regulation of IDE (79). The role of PR in regulating IDE is unclear. Although the PR antagonists RU486 and Org 31710 inhibited P 4 regulation of TTR mRNA, the antagonists failed to block the P 4 -mediated increase in IDE mRNA levels in neuron culture, suggesting that neither of the two PR isoforms A and B mediates this P 4 response. Future work will determine whether the mechanism involves a nonclassical mediator of P 4 action ( e.g. PR membrane component 1) or perhaps P 4 metabolites ( e.g. allopregnanolone). Further investigation of the roles of ER and PR is required to completely understand the mechanism underlying the observed regulation of these A ␤ clearance factors. Our study provides novel insight into the roles of individual and interactive effects of E 2 and P 4 in regulating A ␤ by analyzing their effects on the expression of A ␤ clearance factors. The most significant observation is that both E 2 and P 4 increase IDE mRNA expression in vitro and in vivo . This, taken together with the inverse relationship in vivo between IDE expression and A ␤ levels, suggests an- other possible mechanism by which E 2 and P 4 can affect A ␤ accumulation. Continued investigation of the interactions between E and P in regulating A ␤ production and degradation is essential for optimizing hormone-based strategies for the prevention and/or treatment of ...
Context 6
... paradigms was IDE. To confirm that the observed up-regulation of IDE mRNA by E 2 and P 4 yielded increased protein levels of IDE, we conducted Western blots in both cell culture and brain samples. In neuronal cultures, E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically sig- nificant effects apparent at 0.1 nM (Fig. 6, A and F) [F (5,12) 92.6, P 0.001]. In cultures treated with 10 nM E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) 142.1, P 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects ob- served between concentrations of 0.3 nM and ...
Context 7
... E 2 increased IDE protein in a dose- dependent manner by up to 2-fold with statistically sig- nificant effects apparent at 0.1 nM (Fig. 6, A and F) [F (5,12) 92.6, P 0.001]. In cultures treated with 10 nM E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) 142.1, P 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects ob- served between concentrations of 0.3 nM and 300 nM [F (5,12) 33.4, P 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) 23.9, P 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F ...
Context 8
... In cultures treated with 10 nM E 2 , significant increases in IDE protein occurred within 8 h and were retained across the 48-h experimental period [F (4,10) 142.1, P 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects ob- served between concentrations of 0.3 nM and 300 nM [F (5,12) 33.4, P 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) 23.9, P 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) 20.4, P 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with ...
Context 9
... within 8 h and were retained across the 48-h experimental period [F (4,10) 142.1, P 0.001] (Fig. 6, B and G). Similarly, P 4 induced increased IDE protein with significant effects ob- served between concentrations of 0.3 nM and 300 nM [F (5,12) 33.4, P 0.001] (Fig. 6, C and H) and at ex- posure times between 8 h and 48 h [F (4,10) 23.9, P 0.001] (Fig. 6, D and I). In female rats, IDE levels were significantly affected by treatment [F (3,8) 20.4, P 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVXE 2 ) or P 4 (OVXP 4 ) yielded significant increases in IDE protein levels, with ...
Context 10
... [F (3,8) 20.4, P 0.001]. We observed that the OVX group exhibited a non- significant trend of reduced IDE protein relative to the Sham group. Short-term treatment of OVX rats with E 2 (OVXE 2 ) or P 4 (OVXP 4 ) yielded significant increases in IDE protein levels, with the OVXE 2 group increasing IDE levels significantly higher than the Sham group (Fig. 6, E and ...

Citations

... For instance, lower cerebral 17β-estradiol levels were observed in women with AD aged 80 years or older compared to healthy controls [149]. Progesterone, similarly to estrogens, plays a neuroprotective role through gamma-secretase [150] and the insulin-degrading enzyme (IDE) involved in the metabolism of Aβ [151]. Age-related reduction in progesterone levels in women correlates with the risk of AD [152]. ...
Article
Full-text available
In recent years, there has been a growing interest in the concept of the “gut–brain axis”. In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of “neuroinflammation”. The gut microbiota–brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut–brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain–gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut–brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions.
... Прогестерон и эстрогены оказывают интерактивное влияние на головной мозг, однако взаимодействие между синтетическими прогестинами и 17β-эстрадиолом (Е2) в нейронах изучено недостаточно. Степень выраженности протективного эффекта эстрогенов обусловлена прогестагенным компонентом [18] и снижается пропорционально продолжительности дефицита эстрогенов [19]. В исследовании C.J. Pike на культуре эмбрионов крыс было проанализировано влияние семи клинически значимых прогестагенов на экспрессию мРНК ER, E2-индуцированную нейропротекцию и экспрессию мРНК нейротрофического фактора головного мозга (НФГМ, нейротрофин). ...
Article
Female hypogonadism, as a result of natural or induced shutdown of ovarian function, is a multifaceted problem. A variety of clinical manifestations motivates women to consult doctors of various specialties and solve health problems without focusing on the underlying cause. The financial and economic component of the problem due to a violation of the quality of life of women and a sharp decrease in their ability to work requires the inclusion of the most effective method of treatment. There are a number of MHT regimens and combinations that allow differentiated selection of the drug, taking into account the woman’s health status and her concomitant diseases. The range of biological effects and risks depends on the type and dose of the hormonal drug, duration of use, route of administration, and time of initiation of MHT. As a component of MHT, bioidentical estrogens and gestagens are used, different in their vector of influence, pharmacodynamic and pharmacokinetic profile. The article is devoted to cyclic biphasic MHT using a combination of 17β-estradiol (2 mg) and levonorgestrel (0.15 mg). The experience of using the drug will be presented in the form of a review and our own clinical cases from everyday medical practice.
... Sex steroid hormones, including estrogens, progestins and androgens, have multiple activating effects on the brain, regulate amyloidosis, tauopathy and gliosis, improve neuronal health, and protect against mild cognitive impairment and AD. In addition, sex hormones may act more generally to enhance brain function [19,21,182,[186][187][188][189][190][191]. The renin-angiotensin system has also been involved in AD [192,193]. ...
Article
Full-text available
The aging of the global population is a significant and complex phenomenon with far-reaching implications for healthcare systems and society. By 2030, it is projected that the number of individuals over the age of 65 will increase by nearly 1 billion, largely due to advancements in healthcare and improvements in quality of life. Aging is a multifaceted process that encompasses a wide array of changes, spanning from the cellular level to the intricate physiological systems of the human body. At the central nervous system level, aging represents a major risk factor for conditions such as depression and cognitive impairment, which are likely linked to neuroinflammatory processes and can potentially lead to more severe dementias, including Alzheimer's disease (AD). The higher prevalence of AD in women compared to men has led to speculation that the onset of menopause and associated phenomena, particularly the decline in estrogen levels, may play a role in the development of the disease. Furthermore, research has shown that physical exercise confers both physical and mental health benefits to older adults, with women potentially experiencing the greatest advantages. Understanding the multifaceted nature of aging and its implications for health will ensure that older adults receive the support and care essential for maintaining their health and quality of life.
... In women with AD, plasma levels of estrogen are lower when compared to age-matched controls [358]. Animal models of AD have shown that loss of circulating 17␤-estradiol after ovariectomy is associated with increased AD-like neuropathological changes including amyloid [359,360] as well as decreased cognitive function [361,362]. Treatment with 17␤estradiol after ovariectomy mitigated these effects to varying degrees [359][360][361]. ...
... Animal models of AD have shown that loss of circulating 17␤-estradiol after ovariectomy is associated with increased AD-like neuropathological changes including amyloid [359,360] as well as decreased cognitive function [361,362]. Treatment with 17␤estradiol after ovariectomy mitigated these effects to varying degrees [359][360][361]. Changes in the expression of estrogen receptors in the brain has also been implicated in AD. ...
Chapter
Full-text available
Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.
... Serum and brain testosterone concentrations were significantly lower in the patients than in healthy individuals. In addition, endogenous testosterone deficiency caused by orchiectomy leads to an increase in soluble Aβ concentrations in the rat brains, and androgen administration reduces Aβ concentrations [6,10]. The female hormone, estrogen, is also involved in the risk of developing AD. ...
... The female hormone, estrogen, is also involved in the risk of developing AD. Ovariectomized mice show elevated levels of soluble Aβ in the brain, followed by accelerated accumulation of Aβ and rapid worsening of cognitive behaviors [6,10]. Decreased estrogen levels in adulthood increase the risk of AD. ...
... We found that the effects of sex and ApoE on CM values varied with age, which may be due to the opposing effects of sex hormones and ApoE4 on Aβ accumulation. Sex hormones are known to have inhibitory effects on Aβ formation [9,10,[24][25][26][27]. In males, blood testosterone concentrations and the risk of developing AD have been correlated based on a report that male patients with AD have lower serum testosterone levels [25,26]. ...
Article
Full-text available
Measurement of amyloid concentration in blood using time-of-flight mass spectrometry was developed, and the combined normalized score of amyloid precursor proteins (composite biomarker: CM) in plasma was found to be related to the accumulation of β-amyloid (Aβ) in the brain. Therefore, we measured the CM value in healthy subjects aged 30-79 years and investigated the association between the CM value and clinical characteristics using multiple regression and decision tree analyses. The results indicated that the CM value was associated with age, sex, ApoE genotype, blood glucose, and Mg in healthy subjects. Factors affecting CM values differed by age. The CM values of patients with central nervous system disorders were higher than those of the healthy subjects. Moreover, the relationship between CM and Mg concentrations differed between the patients and healthy subjects. These results suggest that the CM value can be used as a biomarker for the onset of dementia, including Alzheimer's disease. The combination of CM values and blood component results may allow for more accurate diagnosis.
... In women with AD, plasma levels of estrogen are lower when compared to age-matched controls [358]. Animal models of AD have shown that loss of circulating 17␤-estradiol after ovariectomy is associated with increased AD-like neuropathological changes including amyloid [359,360] as well as decreased cognitive function [361,362]. Treatment with 17␤estradiol after ovariectomy mitigated these effects to varying degrees [359][360][361]. ...
... Animal models of AD have shown that loss of circulating 17␤-estradiol after ovariectomy is associated with increased AD-like neuropathological changes including amyloid [359,360] as well as decreased cognitive function [361,362]. Treatment with 17␤estradiol after ovariectomy mitigated these effects to varying degrees [359][360][361]. Changes in the expression of estrogen receptors in the brain has also been implicated in AD. ...
Article
Full-text available
Background Fragmentation of the daily sleep‐wake rhythm is a risk factor for Alzheimer’s disease (AD) (Li et al, Lancet Healthy Longev 1:e96‐e105 [2020]). While women have a higher AD incidence than men, whether women are more sensitive to sleep fragmentation (SF) is not known. Studies in female 3xTg‐AD mice (8‐11 months old) show that chronic SF for four weeks alters the daily sleep‐wake rhythm and stimulates AD‐like neuropathology (Duncan et al, Neuroscience 481:111‐122 [2022]). Method To investigate possible sex differences in the effects of sleep fragmentation, we studied two AD mouse models and matching wild‐type controls, APPxPS1‐knock‐in mice (6.2‐11 months old; N = 127) and 5XFAD mice (2.3‐3.3 months old; N = 52). All mice were exposed to 3‐4 weeks of SF or undisturbed sleep while individually housed in cages interfaced for piezo electric sleep recording for monitoring of daily sleep‐wake rhythms. SF consisted of four daily sessions (1 hour each) of enforced wakefulness (induced with toys and paintbrush stimulation) that were evenly distributed during the light phase, for 5 days/week. Immediately after the last SF session, mice in both groups were euthanized and cortical and hippocampal tissue was dissected and frozen. Amyloid‐beta levels were determined in soluble fractions using ELISA. Results SF redistributed sleep from the light phase (loss) to the dark phase (gain) in APPxPS1‐ki (p<0.0001) and 5XFAD (p<0.05) mice and WT controls. Overall, females slept less than males (p<0.001) and were more affected by SF. Dark phase “rebound” sleep after SF was greater in APPxPS1‐ki females (∼70% of undisturbed controls) than in APPxPS1 males or WT mice of either sex (∼20% of undisturbed controls) (p<0.001). Cortical amyloid‐beta levels were higher in female than male AD mice, but surprisingly, neither cortical nor hippocampal amyloid‐beta levels were affected by SF in either strain. Conclusion These findings suggest an interaction between sex, AD mutations, and neuropathology on dark phase rebound sleep after chronic SF. To elucidate this interaction, on‐going studies are investigating the role of amyloid‐beta in sex‐differences in SF‐induced rebound sleep and potential sex differences in SF effects on gene expression in brain regions regulating sleep or circadian rhythms.
... The evidence suggested by epidemiological studies has been confirmed by experimental animal investigations. This line of research demonstrated that ovariectomized female rodents show increased levels of Aβ 42, an overall acceleration of Aβ accumulation, and a worsening of cognitive performance [93][94][95]. Less information is available from animal models in males, but Rosario et al. [94] demonstrated that the age-related decrease in brain levels of androgens significantly correlated with age-related increases in soluble Aβ. In addition, Ramsden et al. [96] reported that orchiectomy significantly increases soluble Aβ in rodent male brains. ...
... This line of research demonstrated that ovariectomized female rodents show increased levels of Aβ 42, an overall acceleration of Aβ accumulation, and a worsening of cognitive performance [93][94][95]. Less information is available from animal models in males, but Rosario et al. [94] demonstrated that the age-related decrease in brain levels of androgens significantly correlated with age-related increases in soluble Aβ. In addition, Ramsden et al. [96] reported that orchiectomy significantly increases soluble Aβ in rodent male brains. ...
Article
Mild cognitive impairment (MCI) has been frequently interpreted as a transitional phase between healthy cognitive aging and dementia, particularly of the Alzheimer's disease (AD) type. Of note, few studies explored that transition from a multifactorial perspective, taking into consideration the effect of basic factors such as biological sex. In the present study 96 subjects with MCI (37 males and 59 females) were followed-up and divided into two subgroups according to their clinical outcome: “progressive” MCI (pMCI = 41), if they fulfilled the diagnostic criteria for AD at the end of follow-up; and “stable” MCI (sMCI = 55), if they remained with the initial diagnosis. Different markers were combined to characterize sex differences between groups, including magnetoencephalography recordings, cognitive performance, and brain volumes derived from magnetic resonance imaging. Results indicated that the pMCI group exhibited higher low-frequency activity, lower scores in neuropsychological tests and reduced brain volumes than the sMCI group, being these measures significantly correlated. When sex was considered, results revealed that this pattern was mainly due to the influence of the females’ sample. Overall, females exhibited lower cognitive scores and reduced brain volumes. More interestingly, females in the pMCI group showed an increased theta activity that correlated with a more abrupt reduction of cognitive and volumetric scores as compared with females in the sMCI group and with males in the pMCI group. These findings suggest that females’ brains might be more vulnerable to the effects of AD pathology, since regardless of age, they showed signs of more pronounced deterioration than males.
... -Enhancement of the non-amyloidogenic alfa-secretase pathway; -Modulation of γ secretases activities; -Increasing A β clearance by the enhancement insulin-degrading enzyme expression and downregulation of beta-secretase gene expression [41]. ...
Article
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Estradiol promotes neuronal growth, transmission, survival, myelinization, plasticity, synaptogenesis, and dendritic branching and it improves cognitive function. Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and the loss of neuronal connection in the brain. Genomic analysis has concluded that hypoestrogenism influences the APOE gene and increases the risk of AD. Premature ovarian insufficiency (POI) is defined as oligo/amenorrhea in women below 40 years of age, low estradiol, and high-gonadotropin levels. Early symptoms and signs of POI must be detected in time in order to prevent subsequent complications, such as Alzheimer’s disease. Meta-analysis has shown favorable effects of estrogen in preventing Alzheimer’s. We measured some of the typical markers of AD in women with POI such as interleukin 6 (IL-6), interleukin 8 (IL-8), tissue necrosis factor α (TNFα), TAU1, TREM2, and amyloid precursor proteins (APP). While FSH, LH, and IL-8 were significantly higher in POI group, compared to controls, testosterone and DHEAS were lower. A significant decrease in IL-6 was found in the POI group during a 6-month therapy, as well as an increase in amyloid precursor proteins. CONCLUSION: Neurological complications of POI, such as declining short-term memory, cognitive function, and dementia, have to be promptly stopped by initiating estro-progestogen therapy in POI. A long-term continuation of the therapy would be strongly advised.
... These findings 310 imply that the accumulation of Aβ in the brain increases consistently with age, and the 311 consistent increase in the brain is similar to the change in the CM value of males. In 312 females, reduced estrogen levels appear to be associated with an increased risk of AD 313 [6,16]. Estrogen levels decrease sharply during menopause [14]. ...
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Accumulation of β-amyloid (Aβ) in the brain occurs in the early phase of Alzheimer’s disease (AD), without symptoms of cognitive decline. Therefore, early detection of the accumulation phase is essential to prevent or delay AD. In this study, we investigated the effects of age, sex, apoprotein-E (ApoE) genotype and cognitive dysfunction on the ratio of Aβ1-42, Aβ1-40, and amyloid β precursor protein (APP)669-711 (composite biomarker: CM) in plasma using a sensitive Time of flight mass spectrometry (TOF-MS). In healthy subjects, the average CM value of males aged 30–59 years was significantly higher than that of females, but no difference was observed between those aged 60 and 79 years. CM values increased considerably after 50 years of age, especially in females. The effect of the ApoE4 genotype on CM was greater in females than in males. The CM value of patients with AD was higher than that of healthy subjects and that of patients with Parkinson’s disease (PD). The CM value of patients with PD complicated by AD was higher than that of patients with PD. These results suggest that the CM value is influenced by age, sex, ApoE4 genotype, and central nervous system disorder. In addition, the CM value could be a reliable biomarker to distinguish not only patients with AD and healthy subjects but also AD and patients with PD. Since the measurement of CM is less invasive to the subjects, the method is helpful for the early detection of accumulation of Aβ before the appearance of AD symptoms. Moreover, this practical method can be used for differential diagnosis among a variety of patients with dementia.
... Chez les femmes, la ménopause est marquée par une réduction importante de l'oestrogène et de la progestérone qui résulterait chez les souris transgéniques de la MA en une augmentation de l'Aβ (Levin-Allerhand et al., 2002;Yue et al., 2005;Li et al., 2013). En effet, ces deux hormones sont connues pour exercer un rôle protecteur dans la MA en modulant les enzymes impliquées dans la production de l'Aβ, notamment la g-sécrétase, et en stimulant les processus d'élimination de l'amyloïde par l'enzyme de dégradation de l'insuline (IDE) (Jayaraman et al., 2012). L'oestradiol a également une activité protectrice en activant l'a-sécrétase, une enzyme qui empêche la production de l'Aβ, tout en en inhibant la b-sécrétase une enzyme qui joue un rôle central dans la production d'Aβ (Amtul et al., 2010;Jung et al., 2013). ...