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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 exhibits a biphasic profile in CSF of APP transgenic miceA, B Aβ40 and Aβ42 concentrations in CSF of male APP23 mice (heterozygous; 3 (n = 14), 6 (n = 12), 8 (n = 10), 12 (n = 11), 19 (n = 9), and 25 (n = 6) months of age). CSF Aβ40 (F(1, 56) = 22.351, P < 0.001) as well as CSF Aβ42 (F(1, 56) = 38.597, P < 0.001) followed a significant quadratic trend.C Aβ42/40 ratio in CSF of APP23 mice showed a delayed decrease with age (F(1, 56) = 53.894, P < 0.001).D, E Aβ40 and Aβ42 concentrations in CSF of male and female APP24 mice (homozygous; 2 (n = 13), 3–4 (n = 16), 7–8 (n = 15), 18–19 (n = 14), 24 (n = 16), and 30 (n = 18) months of age). CSF Aβ40 followed a significant quadratic trend (F(1, 86) = 6.678, P = 0.011) and CSF Aβ42 best fitted a cubic trend (F(1, 86) = 30.599, P < 0.001).F Aβ42/40 ratio in CSF of APP24 mice showed a delayed decrease with age (F(1, 86) = 64.936, P < 0.001).G, H Aβ40 and Aβ42 in the CSF of female APP51 mice (heterozygous; 3 (n = 6), 15 (n = 8), and 24 (n = 8) months of age; 22 mice in total). CSF Aβ40 (F(1, 19) = 37.349, P < 0.001) as well as CSF Aβ42 (F(1, 19) = 107.670, P < 0.001) followed a significant quadratic trend.I Aβ42/40 ratio in CSF of APP51 mice showed a delayed decrease with age (F(1, 19) = 26.367, P < 0.001).Data information: Post hoc Dunnett's test was employed for group comparisons, which were always conducted between the youngest group and all other groups. (Observed CSF Aβ40 or Aβ42 changes were independent of batch.) All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001.
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fig01: Human Aβ exhibits a biphasic profile in CSF of APP transgenic miceA, B Aβ40 and Aβ42 concentrations in CSF of male APP23 mice (heterozygous; 3 (n = 14), 6 (n = 12), 8 (n = 10), 12 (n = 11), 19 (n = 9), and 25 (n = 6) months of age). CSF Aβ40 (F(1, 56) = 22.351, P < 0.001) as well as CSF Aβ42 (F(1, 56) = 38.597, P < 0.001) followed a significant quadratic trend.C Aβ42/40 ratio in CSF of APP23 mice showed a delayed decrease with age (F(1, 56) = 53.894, P < 0.001).D, E Aβ40 and Aβ42 concentrations in CSF of male and female APP24 mice (homozygous; 2 (n = 13), 3–4 (n = 16), 7–8 (n = 15), 18–19 (n = 14), 24 (n = 16), and 30 (n = 18) months of age). CSF Aβ40 followed a significant quadratic trend (F(1, 86) = 6.678, P = 0.011) and CSF Aβ42 best fitted a cubic trend (F(1, 86) = 30.599, P < 0.001).F Aβ42/40 ratio in CSF of APP24 mice showed a delayed decrease with age (F(1, 86) = 64.936, P < 0.001).G, H Aβ40 and Aβ42 in the CSF of female APP51 mice (heterozygous; 3 (n = 6), 15 (n = 8), and 24 (n = 8) months of age; 22 mice in total). CSF Aβ40 (F(1, 19) = 37.349, P < 0.001) as well as CSF Aβ42 (F(1, 19) = 107.670, P < 0.001) followed a significant quadratic trend.I Aβ42/40 ratio in CSF of APP51 mice showed a delayed decrease with age (F(1, 19) = 26.367, P < 0.001).Data information: Post hoc Dunnett's test was employed for group comparisons, which were always conducted between the youngest group and all other groups. (Observed CSF Aβ40 or Aβ42 changes were independent of batch.) 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 exhibits a biphasic profile in CSF of APP transgenic miceA, B Aβ40 and Aβ42 concentrations in CSF of male APP23 mice (heterozygous; 3 (n = 14), 6 (n = 12), 8 (n = 10), 12 (n = 11), 19 (n = 9), and 25 (n = 6) months of age). CSF Aβ40 (F(1, 56) = 22.351, P < 0.001) as well as CSF Aβ42 (F(1, 56) = 38.597, P < 0.001) followed a significant quadratic trend.C Aβ42/40 ratio in CSF of APP23 mice showed a delayed decrease with age (F(1, 56) = 53.894, P < 0.001).D, E Aβ40 and Aβ42 concentrations in CSF of male and female APP24 mice (homozygous; 2 (n = 13), 3–4 (n = 16), 7–8 (n = 15), 18–19 (n = 14), 24 (n = 16), and 30 (n = 18) months of age). CSF Aβ40 followed a significant quadratic trend (F(1, 86) = 6.678, P = 0.011) and CSF Aβ42 best fitted a cubic trend (F(1, 86) = 30.599, P < 0.001).F Aβ42/40 ratio in CSF of APP24 mice showed a delayed decrease with age (F(1, 86) = 64.936, P < 0.001).G, H Aβ40 and Aβ42 in the CSF of female APP51 mice (heterozygous; 3 (n = 6), 15 (n = 8), and 24 (n = 8) months of age; 22 mice in total). CSF Aβ40 (F(1, 19) = 37.349, P < 0.001) as well as CSF Aβ42 (F(1, 19) = 107.670, P < 0.001) followed a significant quadratic trend.I Aβ42/40 ratio in CSF of APP51 mice showed a delayed decrease with age (F(1, 19) = 26.367, P < 0.001).Data information: Post hoc Dunnett's test was employed for group comparisons, which were always conducted between the youngest group and all other groups. (Observed CSF Aβ40 or Aβ42 changes were independent of batch.) All data are represented as group means ± SEM; *P < 0.05; **P < 0.01; and ***P < 0.001.
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fig01: Human Aβ exhibits a biphasic profile in CSF of APP transgenic miceA, B Aβ40 and Aβ42 concentrations in CSF of male APP23 mice (heterozygous; 3 (n = 14), 6 (n = 12), 8 (n = 10), 12 (n = 11), 19 (n = 9), and 25 (n = 6) months of age). CSF Aβ40 (F(1, 56) = 22.351, P < 0.001) as well as CSF Aβ42 (F(1, 56) = 38.597, P < 0.001) followed a significant quadratic trend.C Aβ42/40 ratio in CSF of APP23 mice showed a delayed decrease with age (F(1, 56) = 53.894, P < 0.001).D, E Aβ40 and Aβ42 concentrations in CSF of male and female APP24 mice (homozygous; 2 (n = 13), 3–4 (n = 16), 7–8 (n = 15), 18–19 (n = 14), 24 (n = 16), and 30 (n = 18) months of age). CSF Aβ40 followed a significant quadratic trend (F(1, 86) = 6.678, P = 0.011) and CSF Aβ42 best fitted a cubic trend (F(1, 86) = 30.599, P < 0.001).F Aβ42/40 ratio in CSF of APP24 mice showed a delayed decrease with age (F(1, 86) = 64.936, P < 0.001).G, H Aβ40 and Aβ42 in the CSF of female APP51 mice (heterozygous; 3 (n = 6), 15 (n = 8), and 24 (n = 8) months of age; 22 mice in total). CSF Aβ40 (F(1, 19) = 37.349, P < 0.001) as well as CSF Aβ42 (F(1, 19) = 107.670, P < 0.001) followed a significant quadratic trend.I Aβ42/40 ratio in CSF of APP51 mice showed a delayed decrease with age (F(1, 19) = 26.367, P < 0.001).Data information: Post hoc Dunnett's test was employed for group comparisons, which were always conducted between the youngest group and all other groups. (Observed CSF Aβ40 or Aβ42 changes were independent of batch.) 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