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Comparative Study
. 2009 Jul;110(2):653-61.
doi: 10.1111/j.1471-4159.2009.06158.x. Epub 2009 May 11.

Dkk-3 is elevated in CSF and plasma of Alzheimer's disease patients

Christoph Zenzmaier  1 , Josef Marksteiner, Andreas Kiefer, Peter Berger, Christian Humpel
Affiliations
Comparative Study

Dkk-3 is elevated in CSF and plasma of Alzheimer's disease patients

Christoph Zenzmaier et al. J Neurochem. 2009 Jul.

Abstract

Biomarkers in CSF can offer improved diagnostic accuracy for Alzheimer's disease (AD). The present study investigated whether the glycoprotein and putative tumor suppressor Dickkopf homolog 3 (Dkk-3) is secreted into CSF and evaluated its applicability as a diagnostic marker for AD. Using our highly specific immunoenzymometric assay, Dkk-3 levels were measured in plasma and/or CSF of patients suffering from depression, mild cognitive impairment (MCI), or AD and compared with healthy subjects. Dkk-3 identity was verified by western blot and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)/MS. High concentrations of Dkk-3 were detected in CSF compared with plasma (28.2 +/- 1.3 vs. 1.22 +/- 0.04 nmol/L, respectively). Consistently Dkk-3 expression was demonstrated in neurons of the cortex and epithelial cells of the choroid plexus, the major source of CSF. Significantly increased Dkk-3 levels in plasma and CSF were observed for AD patients compared with healthy subjects but not patients suffering from MCI or depression. In summary, our data indicate that elevated Dkk-3 levels are specifically associated with AD and might serve as a potential non-invasive AD biomarker in plasma.

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Figures

Fig. 1
Fig. 1
High levels of Dkk-3 in CSF. (a) Dkk-3 levels of control probands were ~25-fold higher in CSF (28.2 ± 1.3 nmol/L; n = 26) compared with plasma (1.21 ± 0.04 nmol/L; n = 25). (b). A total of 2 μL of CSF (containing ~80 pmol Dkk-3) and 80 pmol of recDkk-3 were analyzed by western blotting. Dkk-3 in CSF equals the recombinant protein in size (~70 kDa) and signal intensity. Signals in both samples can be completely blocked by direct competition with 50-fold excess of recDkk-3, demonstrating the specificity of our mAb (Zenzmaier et al. 2008a). (c) Dkk-3 content of CSF did not change significantly with age, when comparing control individuals < 55 years (26.4 ± 2.3 nmol/L; n = 7), 55–65 years (30.0 ± 1.9 nmol/L; n = 11), and > 65 years (27.2 ± 2.5 nmol/L; n = 8).
Fig. 2
Fig. 2
Localization of Dkk-3 in brain tissue. Areas of the frontal cortex (a), the hippocampus (b and c) and the choroid plexus were immunohistochemically probed for Dkk-3 and counterstained with Mayer’s Hemalum. Specificity controls of the mouse mAb Dkk3-1 were performed by blocking experiments with an excess of recDkk-3 (right panel). Strong signals for Dkk-3 were detected in neurons of the isocortex and in the Ammon’s horn of the hippocampus. In the later, Dkk-3 was mainly expressed in pyramidal cells (c: detail of Cornu Ammonis area CA2). Furthermore, Dkk-3 was strongly expressed in epithelial cells of the choroid plexus. Original magnifications: (a and b), 40× and (c and d), 200×.
Fig. 3
Fig. 3
Dkk-3 and β-amyloid (1–42) levels as classifiers for diagnosis. (a) ROC curve for the classification of AD patients versus control subjects based on Dkk-3 plasma levels. (b) A one-dimensional scatter plot of β-amyloid (1–42) levels (individual levels marked with ‘x’; mean values with ‘–’) revealed high heterogeneity of the single patient cohorts. (c) A one-dimensional scatter plot of the ratio of β-amyloid (1–42) levels/Dkk-3 levels showed less heterogeneity of the single patient cohorts. (d–e) ROC curves for the classification of (d) MCI and (e) AD patients versus control subjects and (f) MCI versus AD patients based on β-amyloid (1–42) levels and the ratio β-amyloid (1–42)/Dkk-3, respectively.
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