Increased Dickkopf‐1 expression in transgenic mouse models of neurodegenerative disease

Abstract

J. Neurochem. (2010) 112, 1539–1551. Abstract To investigate the role of the Wnt inhibitor Dickkopf‐1 (DKK‐1) in the pathophysiology of neurodegenerative diseases, we analysed DKK‐1 expression and localization in transgenic mouse models expressing familial Alzheimer’s disease mutations and a frontotemporal dementia mutation. A significant increase of DKK‐1 expression was found in the diseased brain areas of all transgenic lines, where it co‐localized with hyperphosphorylated tau‐bearing neurons. In TgCRND8 mice, DKK‐1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase‐positive neurons of the basal forebrain. Active glycogen synthase kinase‐3 (GSK‐3) was found to co‐localize with DKK‐1 and phospho‐tau staining. Downstream to GSK‐3, a significant reduction in β‐catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK‐1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK‐1 as a key mediator of neurodegeneration with therapeutic potential.

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…In this model, Aß deposits increase over time and become robust by 7e9 months of age (Bellucci et al, 2007;Rosi et al, 2010). We have previously reported that OLE administration in young and middle-aged TgCRND8 mice results in remarkably beneficial behavioral, molecular, and histopathologic effects, suggesting that it could be useful to treat patients with presymptomatic or early AD (Grossi et al, 2013).…”

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

“…This LRP6 variant confers low levels of Wnt signaling. Consistent with reduced Wnt signaling, the secreted Wnt antagonist Dickkopf-1 (Dkk1) is elevated in postmortem AD brains and brains from transgenic mouse models for AD (Caricasole et al, 2004;Rosi et al, 2010). Importantly, Dkk1 blocks canonical Wnt signaling by binding to LRP6 (Niehrs, 2006).…”

“…Importantly, Dkk1 blocks canonical Wnt signaling by binding to LRP6 (Niehrs, 2006). Although the mechanism of Dkk1 in AD is unclear, it has been proposed that Dkk1 might contribute to AD by promoting cell death (Caricasole et al, 2004;Rosi et al, 2010). However, given the role of Wnt signaling on synapses, elevation of Dkk1 could induce synaptic disassembly in early stages of AD.…”

“…The expression of the secreted Wnt antagonist Dkk1 is increased in the hippocampus of transgenic mouse models for AD (Rosi et al, 2010). We therefore examined whether A␤ directly regulates Dkk1 expression in acute brain slices by using A␤-derived diffusible ligands (defined here as A␤).…”

Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors

“…Such inhibitors include sclerostin, sclerostin-domain containing, and the DKK family of inhibitors (2). The importance of these inhibitors has been emphasized by studies linking changes in their expression to significant defects in development, homeostatic regulation, or cancer prognosis (17)(18)(19)(20)(21). Sclerostin is an osteocyte-produced extracellular glycoprotein of 190 amino acids that negatively regulates the anabolic output of bone-forming osteoblasts (22)).…”