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Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models.

Maia LF, Kaeser SA, Reichwald J, Lambert M, Obermüller U, Schelle J, Odenthal J, Martus P, Staufenbiel M, Jucker M - EMBO Mol Med (2015)

Bottom Line: However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective.Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20-30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models.Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany Department of Neurology, Hospital de Santo António-CHP, Porto, Portugal luis.maia@medizin.uni-tuebingen.de mathias.jucker@uni-tuebingen.de.

No MeSH data available.


Related in: MedlinePlus

Brain sAPPβ shows an age-related increase in APP23, APP24, and APP51 micesAPPβ was measured in Triton X-100 brain extracts from largely the same mice as analyzed in Figs1 and 2 and is expressed as percentages of levels measured in the youngest age group.Swedish sAPPβ showed an age-dependent increase in APP23 mice following a linear trend (F(1, 83) = 52.914, P < 0.001); APP23 from two independent batches were included in this analysis (see Materials and Methods and Supplementary Fig S2 for details).Swedish sAPPβ showed an age-dependent increase in APP24 mice following a linear trend (F(1, 84) = 11.264, P = 0.001).Human wild-type sAPPβ showed an age-dependent increase in APP51 following a quadratic trend (F(1, 18) = 68.980, P < 0.001).Data information: Post hoc Dunnett's test group comparisons were always conducted between the youngest group and all other groups. All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001. For absolute values, see Supplementary Fig S2.
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fig04: Brain sAPPβ shows an age-related increase in APP23, APP24, and APP51 micesAPPβ was measured in Triton X-100 brain extracts from largely the same mice as analyzed in Figs1 and 2 and is expressed as percentages of levels measured in the youngest age group.Swedish sAPPβ showed an age-dependent increase in APP23 mice following a linear trend (F(1, 83) = 52.914, P < 0.001); APP23 from two independent batches were included in this analysis (see Materials and Methods and Supplementary Fig S2 for details).Swedish sAPPβ showed an age-dependent increase in APP24 mice following a linear trend (F(1, 84) = 11.264, P = 0.001).Human wild-type sAPPβ showed an age-dependent increase in APP51 following a quadratic trend (F(1, 18) = 68.980, P < 0.001).Data information: Post hoc Dunnett's test group comparisons were always conducted between the youngest group and all other groups. All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001. For absolute values, see Supplementary Fig S2.

Mentions: To determine whether the age-related changes in CSF Aβ concentration may reflect changes in the amyloidogenic APP processing pathway, brain sAPPβ was measured (Bodendorf et al, 2002). Overall, we found a significant age-related increase in sAPPβ in all of the models that appeared to be more prominent in APP23 and APP51 mice (Fig4; Supplementary Fig S2). While the changes in sAPPβ did not allow to demonstrate a consistent relation to the onset of plaque formation, it is possible that the initial increase in CSF Aβ40 and Aβ42 is governed by an increase in Aβ generation via the amyloidogenic APP processing pathway. The decline of CSF Aβ that follows the increase (more prominent for Aβ42 than 40) may then be caused by Aβ deposition onto amyloid plaques (sequestering hypothesis). As plaques and their Aβ binding sites increase, Aβ sequestration also goes up and eventually outbalances the increase in Aβ with aging in all the models. This then leads to the decline of soluble Aβ that reaches the CSF.


Increased CSF Aβ during the very early phase of cerebral Aβ deposition in mouse models.

Maia LF, Kaeser SA, Reichwald J, Lambert M, Obermüller U, Schelle J, Odenthal J, Martus P, Staufenbiel M, Jucker M - EMBO Mol Med (2015)

Brain sAPPβ shows an age-related increase in APP23, APP24, and APP51 micesAPPβ was measured in Triton X-100 brain extracts from largely the same mice as analyzed in Figs1 and 2 and is expressed as percentages of levels measured in the youngest age group.Swedish sAPPβ showed an age-dependent increase in APP23 mice following a linear trend (F(1, 83) = 52.914, P < 0.001); APP23 from two independent batches were included in this analysis (see Materials and Methods and Supplementary Fig S2 for details).Swedish sAPPβ showed an age-dependent increase in APP24 mice following a linear trend (F(1, 84) = 11.264, P = 0.001).Human wild-type sAPPβ showed an age-dependent increase in APP51 following a quadratic trend (F(1, 18) = 68.980, P < 0.001).Data information: Post hoc Dunnett's test group comparisons were always conducted between the youngest group and all other groups. All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001. For absolute values, see Supplementary Fig S2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4520655&req=5

fig04: Brain sAPPβ shows an age-related increase in APP23, APP24, and APP51 micesAPPβ was measured in Triton X-100 brain extracts from largely the same mice as analyzed in Figs1 and 2 and is expressed as percentages of levels measured in the youngest age group.Swedish sAPPβ showed an age-dependent increase in APP23 mice following a linear trend (F(1, 83) = 52.914, P < 0.001); APP23 from two independent batches were included in this analysis (see Materials and Methods and Supplementary Fig S2 for details).Swedish sAPPβ showed an age-dependent increase in APP24 mice following a linear trend (F(1, 84) = 11.264, P = 0.001).Human wild-type sAPPβ showed an age-dependent increase in APP51 following a quadratic trend (F(1, 18) = 68.980, P < 0.001).Data information: Post hoc Dunnett's test group comparisons were always conducted between the youngest group and all other groups. All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001. For absolute values, see Supplementary Fig S2.
Mentions: To determine whether the age-related changes in CSF Aβ concentration may reflect changes in the amyloidogenic APP processing pathway, brain sAPPβ was measured (Bodendorf et al, 2002). Overall, we found a significant age-related increase in sAPPβ in all of the models that appeared to be more prominent in APP23 and APP51 mice (Fig4; Supplementary Fig S2). While the changes in sAPPβ did not allow to demonstrate a consistent relation to the onset of plaque formation, it is possible that the initial increase in CSF Aβ40 and Aβ42 is governed by an increase in Aβ generation via the amyloidogenic APP processing pathway. The decline of CSF Aβ that follows the increase (more prominent for Aβ42 than 40) may then be caused by Aβ deposition onto amyloid plaques (sequestering hypothesis). As plaques and their Aβ binding sites increase, Aβ sequestration also goes up and eventually outbalances the increase in Aβ with aging in all the models. This then leads to the decline of soluble Aβ that reaches the CSF.

Bottom Line: However, there is little information on the longitudinal dynamics of CSF biomarkers, especially in the earliest disease stages when therapeutic interventions are likely most effective.Remarkably, while we confirmed the CSF Aβ decrease during the extended course of brain Aβ deposition, a 20-30% increase in CSF Aβ40 and Aβ42 was found around the time of the first Aβ plaque appearance in all models.Ultimately, our findings may open new perspectives in identifying subjects at risk for AD significantly earlier, and in improving the stratification of patients for preventive treatment strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Neurology, Hertie Institute for Clinical Brain Research University of Tübingen, Tübingen, Germany DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany Department of Neurology, Hospital de Santo António-CHP, Porto, Portugal luis.maia@medizin.uni-tuebingen.de mathias.jucker@uni-tuebingen.de.

No MeSH data available.


Related in: MedlinePlus