Dickkopf 3 (Dkk3) Improves Amyloid-beta Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer's Disease

摘要

Dysfunctional Wnt signaling is associated with Alzheimer's disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-beta, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3 beta, a central negative regulator in canonical Wnt signaling, and upregulated PKC beta 1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3 beta and the inhibition of PKC beta 1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD.