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

Amyloid-beta (A beta) is the most prominent protein in Alzheimer's disease (AD) senile plaques. In addition, A beta interacts with a variety of A beta-associated proteins (AAPs), some of which can form complexes with A beta 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 A beta. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Ab in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential A beta-associated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Ab 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 Ab-associated protein which, given its relatively high cerebral concentrations and co-localization with Ab, is potentially involved in AD pathology.