Dickkopf 3 (Dkk3) Improves Amyloid-β Pathology, Cognitive Dysfunction, and Cerebral Glucose Metabolism in a Transgenic Mouse Model of Alzheimer's Disease.
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-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 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.
['Zhang|Li|L|', 'Sun|Caixian|C|', 'Jin|Yaxi|Y|', 'Gao|Kai|K|', 'Shi|Xudong|X|', 'Qiu|Wenying|W|', 'Ma|Chao|C|', 'Zhang|Lianfeng|L|']
D048868:Adaptor Proteins, Signal Transducing D000369:Aged, 80 and over D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D016564:Amyloid beta-Protein Precursor D000818:Animals D002540:Cerebral Cortex D003072:Cognition Disorders D004195:Disease Models, Animal D005106:Exploratory Behavior D005260:Female D005786:Gene Expression Regulation D005947:Glucose D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D008297:Male D018782:Maze Learning D051379:Mice D008822:Mice, Transgenic D009154:Mutation D053764:Presenilin-1 D060449:Wnt Signaling Pathway
Dkk3 cognition Wnt signaling pathway transgenic mice Alzheimer’s disease