PMC:6194691 / 157889-160952 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-11120756-30706524","span":{"begin":425,"end":427},"obj":"11120756"},{"id":"30340614-17077814-30706525","span":{"begin":831,"end":834},"obj":"17077814"},{"id":"30340614-24136970-30706526","span":{"begin":987,"end":990},"obj":"24136970"},{"id":"30340614-11120756-30706527","span":{"begin":1647,"end":1649},"obj":"11120756"},{"id":"30340614-17077814-30706528","span":{"begin":1665,"end":1668},"obj":"17077814"},{"id":"30340614-24136970-30706529","span":{"begin":1712,"end":1715},"obj":"24136970"},{"id":"30340614-11120756-30706530","span":{"begin":1748,"end":1750},"obj":"11120756"},{"id":"30340614-24136970-30706531","span":{"begin":1787,"end":1790},"obj":"24136970"},{"id":"30340614-25205593-30706532","span":{"begin":1995,"end":1998},"obj":"25205593"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Relative importance of metabolism, blood–brain barrier transport and the perivascular route for elimination of soluble Aβ\nAttempts have been made to estimate the proportions of soluble Aβ removed from the brain by metabolism, by transport across the blood–brain barrier, and by perivascular efflux. It is possible to get an estimate of perivascular elimination alone using inulin. When this was done in mice, Shibata et al. [62] found that the half-time for the elimination of 125I-Aβ1-40 was much shorter than could be explained by elimination by the perivascular route, with calculated rate constants of 0.027 min−1 and 0.0029 min−1 respectively (see Table 5). As they had concluded that metabolism played little part, the faster, non-perivascular elimination was held to be transfer across the blood–brain barrier. Bell et al. [429] (see Appendix 2 in [146] for corrections to their calculations) extended these observations to 125I-Aβ1-42.\nIt is interesting to note that Xie et al. [128] found the half-lives for both Aβ and inulin to be different when the mice were asleep as compared to when they were awake. In both conditions the rate constant was larger for Aβ than for inulin (see Table 5). The interpretation of these differences in rate constants between wakefulness and sleep has been considered in some detail in [146] and will not be considered further here.\nTable 5 Rate constants for elimination of 125I-Aβ1-40, 125I-Aβ1-42 and inulin in mice\nRate constant/min−1\nShibtata et al. Bell et al. Xie et al. awake Xie et al. asleep\nInulin 0.0029 0.0024 0.006 0.016\nAβ1-40 0.027 0.0184 0.024 0.053\nAβ1-42 0.011\nData from Shibata et al. [62], Bell et al. [429] (see Appendix 2 of [146]) and Xie et al. [128]\nThe results of Shibata et al. [62], Iliff et al. [25] and Xie et al. [128] all imply that the rate constant of perivascular elimination, as estimated by the constant for inulin efflux, is considerably less than the rate constant of elimination by other means.21\nRoberts et al. [457] sought to compare rates of metabolism of Aβ with those of Aβ efflux. To do this they used values for: the turnover rate for Aβ [512]; the pool size for Aβ; the difference between Aβ concentrations in arterial blood and in venous blood leaving the brain; the cerebral blood flow and the rate of return of CSF to the general circulation. From these values they calculated that 25% of Aβ elimination was via efflux across the blood–brain barrier, 25% was via CSF and the remaining 50% was via metabolism. As discussed in [146] while the results of Roberts et al. do suggest that all of these mechanisms are involved, the fraction of Aβ leaving the brain across the blood–brain barrier may have been underestimated and could be as high as 50%. By contrast the fraction accounted for by metabolism may have been smaller than estimated.\nOn balance the available data suggests a significant involvement in elimination of Aβ from the brain for all three routes of elimination: metabolism, net outward flux across the blood–brain barrier and net perivascular outward flux."}

{"project":"2_test","denotations":[{"id":"30340614-11120756-30706524","span":{"begin":425,"end":427},"obj":"11120756"},{"id":"30340614-17077814-30706525","span":{"begin":831,"end":834},"obj":"17077814"},{"id":"30340614-24136970-30706526","span":{"begin":987,"end":990},"obj":"24136970"},{"id":"30340614-11120756-30706527","span":{"begin":1647,"end":1649},"obj":"11120756"},{"id":"30340614-17077814-30706528","span":{"begin":1665,"end":1668},"obj":"17077814"},{"id":"30340614-24136970-30706529","span":{"begin":1712,"end":1715},"obj":"24136970"},{"id":"30340614-11120756-30706530","span":{"begin":1748,"end":1750},"obj":"11120756"},{"id":"30340614-24136970-30706531","span":{"begin":1787,"end":1790},"obj":"24136970"},{"id":"30340614-25205593-30706532","span":{"begin":1995,"end":1998},"obj":"25205593"}],"text":"Relative importance of metabolism, blood–brain barrier transport and the perivascular route for elimination of soluble Aβ\nAttempts have been made to estimate the proportions of soluble Aβ removed from the brain by metabolism, by transport across the blood–brain barrier, and by perivascular efflux. It is possible to get an estimate of perivascular elimination alone using inulin. When this was done in mice, Shibata et al. [62] found that the half-time for the elimination of 125I-Aβ1-40 was much shorter than could be explained by elimination by the perivascular route, with calculated rate constants of 0.027 min−1 and 0.0029 min−1 respectively (see Table 5). As they had concluded that metabolism played little part, the faster, non-perivascular elimination was held to be transfer across the blood–brain barrier. Bell et al. [429] (see Appendix 2 in [146] for corrections to their calculations) extended these observations to 125I-Aβ1-42.\nIt is interesting to note that Xie et al. [128] found the half-lives for both Aβ and inulin to be different when the mice were asleep as compared to when they were awake. In both conditions the rate constant was larger for Aβ than for inulin (see Table 5). The interpretation of these differences in rate constants between wakefulness and sleep has been considered in some detail in [146] and will not be considered further here.\nTable 5 Rate constants for elimination of 125I-Aβ1-40, 125I-Aβ1-42 and inulin in mice\nRate constant/min−1\nShibtata et al. Bell et al. Xie et al. awake Xie et al. asleep\nInulin 0.0029 0.0024 0.006 0.016\nAβ1-40 0.027 0.0184 0.024 0.053\nAβ1-42 0.011\nData from Shibata et al. [62], Bell et al. [429] (see Appendix 2 of [146]) and Xie et al. [128]\nThe results of Shibata et al. [62], Iliff et al. [25] and Xie et al. [128] all imply that the rate constant of perivascular elimination, as estimated by the constant for inulin efflux, is considerably less than the rate constant of elimination by other means.21\nRoberts et al. [457] sought to compare rates of metabolism of Aβ with those of Aβ efflux. To do this they used values for: the turnover rate for Aβ [512]; the pool size for Aβ; the difference between Aβ concentrations in arterial blood and in venous blood leaving the brain; the cerebral blood flow and the rate of return of CSF to the general circulation. From these values they calculated that 25% of Aβ elimination was via efflux across the blood–brain barrier, 25% was via CSF and the remaining 50% was via metabolism. As discussed in [146] while the results of Roberts et al. do suggest that all of these mechanisms are involved, the fraction of Aβ leaving the brain across the blood–brain barrier may have been underestimated and could be as high as 50%. By contrast the fraction accounted for by metabolism may have been smaller than estimated.\nOn balance the available data suggests a significant involvement in elimination of Aβ from the brain for all three routes of elimination: metabolism, net outward flux across the blood–brain barrier and net perivascular outward flux."}