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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

Human Aβ in CSF and brain of APP transgenic miceA APP23 CSF Aβ40 and Aβ42 in the same animals as shown in Fig1. CSF Aβ42 and Aβ40 are expressed as percentages of levels measured in the youngest age group.B, C Aβ40 and Aβ42 (pmol/g wet brain) in the FA-soluble brain extract from the same APP23 mice showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 56) = 221.114, P < 0.001 and F(1, 56) = 370.947, P < 0.001, respectively).D APP24 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentage of the youngest age group.E, F Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP24 mice also showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 86) = 202.173, P < 0.001 and F(1, 86) = 139.941, P < 0.001, respectively).G APP51 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentages of levels in the youngest age group.H, I Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP51 mice showed a robust increase with age; ANOVA revealed a significant quadratic trend (F(1, 19) = 12.960, P = 0.002 and F(1, 19) = 19.366, P < 0.001, respectively).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.
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fig02: Human Aβ in CSF and brain of APP transgenic miceA APP23 CSF Aβ40 and Aβ42 in the same animals as shown in Fig1. CSF Aβ42 and Aβ40 are expressed as percentages of levels measured in the youngest age group.B, C Aβ40 and Aβ42 (pmol/g wet brain) in the FA-soluble brain extract from the same APP23 mice showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 56) = 221.114, P < 0.001 and F(1, 56) = 370.947, P < 0.001, respectively).D APP24 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentage of the youngest age group.E, F Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP24 mice also showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 86) = 202.173, P < 0.001 and F(1, 86) = 139.941, P < 0.001, respectively).G APP51 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentages of levels in the youngest age group.H, I Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP51 mice showed a robust increase with age; ANOVA revealed a significant quadratic trend (F(1, 19) = 12.960, P = 0.002 and F(1, 19) = 19.366, P < 0.001, respectively).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.

Mentions: APP23 mice expressing human APP with the Swedish mutation were used to test for CSF Aβ40 and Aβ42 changes prior to and during early plaque formation (Sturchler-Pierrat et al, 1997). Both Aβ peptides increased in these mice up to 8 months of age, followed by a steady decline that was more pronounced for Aβ42 than for Aβ40 (Fig1A and B). At the peak concentrations (8 months), there was a 22% increase for both CSF Aβ40 (95% CI: 110–134) and Aβ42 (95% CI: 108–136) compared to the 3-month-old group (Fig1A and B). This inverted U-shaped pattern followed a significant quadratic trend for both CSF Aβ40 and Aβ42 (Fig1A and B, see also Fig2A). The CSF Aβ42/40 ratio did not change until 8 months of age but decreased thereafter (Fig1C).


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)

Human Aβ in CSF and brain of APP transgenic miceA APP23 CSF Aβ40 and Aβ42 in the same animals as shown in Fig1. CSF Aβ42 and Aβ40 are expressed as percentages of levels measured in the youngest age group.B, C Aβ40 and Aβ42 (pmol/g wet brain) in the FA-soluble brain extract from the same APP23 mice showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 56) = 221.114, P < 0.001 and F(1, 56) = 370.947, P < 0.001, respectively).D APP24 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentage of the youngest age group.E, F Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP24 mice also showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 86) = 202.173, P < 0.001 and F(1, 86) = 139.941, P < 0.001, respectively).G APP51 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentages of levels in the youngest age group.H, I Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP51 mice showed a robust increase with age; ANOVA revealed a significant quadratic trend (F(1, 19) = 12.960, P = 0.002 and F(1, 19) = 19.366, P < 0.001, respectively).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.
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fig02: Human Aβ in CSF and brain of APP transgenic miceA APP23 CSF Aβ40 and Aβ42 in the same animals as shown in Fig1. CSF Aβ42 and Aβ40 are expressed as percentages of levels measured in the youngest age group.B, C Aβ40 and Aβ42 (pmol/g wet brain) in the FA-soluble brain extract from the same APP23 mice showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 56) = 221.114, P < 0.001 and F(1, 56) = 370.947, P < 0.001, respectively).D APP24 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentage of the youngest age group.E, F Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP24 mice also showed a robust increase with age; ANOVA revealed a significant cubic trend (F(1, 86) = 202.173, P < 0.001 and F(1, 86) = 139.941, P < 0.001, respectively).G APP51 CSF Aβ40 and Aβ42 in the same animals shown in Fig1 as percentages of levels in the youngest age group.H, I Aβ40 and Aβ42 (pmol/g wet brain) in the brain from the same APP51 mice showed a robust increase with age; ANOVA revealed a significant quadratic trend (F(1, 19) = 12.960, P = 0.002 and F(1, 19) = 19.366, P < 0.001, respectively).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.
Mentions: APP23 mice expressing human APP with the Swedish mutation were used to test for CSF Aβ40 and Aβ42 changes prior to and during early plaque formation (Sturchler-Pierrat et al, 1997). Both Aβ peptides increased in these mice up to 8 months of age, followed by a steady decline that was more pronounced for Aβ42 than for Aβ40 (Fig1A and B). At the peak concentrations (8 months), there was a 22% increase for both CSF Aβ40 (95% CI: 110–134) and Aβ42 (95% CI: 108–136) compared to the 3-month-old group (Fig1A and B). This inverted U-shaped pattern followed a significant quadratic trend for both CSF Aβ40 and Aβ42 (Fig1A and B, see also Fig2A). The CSF Aβ42/40 ratio did not change until 8 months of age but decreased thereafter (Fig1C).

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