Dickkopf‐related protein 3 is a potential Aβ‐associated protein in Alzheimer's Disease

Amyloid-β (Aβ) is the most prominent protein in Alzheimer's disease (AD) senile plaques. In addition, Aβ interacts with a variety of Aβ-associated proteins (AAPs), some of which can form complexes with Aβ and influence its clearance, aggregation or toxicity. Identification of novel AAPs may shed new light on the pathophysiology of AD and the metabolic fate of Aβ. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Aβ in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential Aβ-associated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Aβ in the brain, both in diffuse and classic plaques. (ii) Dkk-3 is expressed in neurons and in blood vessel walls in the brain and (iii) is secreted by leptomeningeal smooth muscle cells in vitro. Finally, measurements using ELISA revealed that (iv) Dkk-3 protein is abundantly present in both cerebrospinal fluid and serum, but its levels are similar in non-demented controls and patients with AD, Lewy body dementia, and frontotemporal dementia. Our study demonstrates that Dkk-3 is a hitherto unidentified Aβ-associated protein which, given its relatively high cerebral concentrations and co-localization with Aβ, is potentially involved in AD pathology. In this study, we propose that Dickkopf-related protein-3 (Dkk-3) might be a novel Amyloid-β (Aβ) associated protein. We demonstrate that Dkk-3 is expressed in the brain, especially in vessel walls, and co-localizes with Aβ in senile plaques. Furthermore, Dkk-3 levels in cerebrospinal fluid strongly correlate with Aβ40 levels, but were not suitable to discriminate non-demented controls and patients with dementia.