Dickkopf-1 accentuates neuronal damage upon multifocal cerebral microinfarctions by impairing vascular and immune responses

Cerebral small vessel disease (cSVD) associated with the occlusion of small penetrating arterioles leading to multifocal microinfarcts, constitutes common microangiopathies affecting brain functions. Dickkopf-1 (DKK1) is a potent inhibitor of the canonical Wnt pathway, which plays key roles in regulating neurovascular and immune functions. DKK1 levels are reported to be increased in cerebrovascular diseases, correlating with poor prognosis. Herein, we aimed to investigate the contribution of DKK1 elevated levels to the pathobiology of cSVD associated with microinfarcts. This was achieved using a transgenic mouse model that enables a conditional tissue-specific induction of DKK1. cSVD was induced via intravascular injection of micro-emboli to occlude penetrating arterioles. Our results indicate that the circulating levels of endogenous DKK1 are increased after cSVD and remain steadily elevated before progressively returning to basal levels. DKK1 conditional induction with respect to its temporal regulation after cSVD exacerbates vascular permeability and alters immediate cerebrovascular reactivity, outlining deregulation of the neurovascular functions. Furthermore, DKK1 induction promotes progressive neuronal loss and impairs neurogenesis after cSVD. We show that DKK1 elevated levels are associated with attenuation of myeloid cell recruitment to the lesion sites, accompanied with a persistent polarization of monocytes in the blood circulation towards a pro-inflammatory phenotype. Notably, we reveal that DKK1 elevated levels for a prolonged period after cSVD mediates pathological changes that remain persistent despite delayed normalization of its expression. Our study suggests that circulating DKK1 decisively affects the pathobiology of cSVD associated with microinfarcts, outlining its potential as a prognostic marker and a therapeutic target.