Role of Wnt Signaling in Adult Hippocampal Neurogenesis in Health and Disease

Abstract

Neurogenesis persists during adulthood in the dentate gyrus of the hippocampus. Signals provided by the local hippocampal microenvironment support neural stem cell proliferation, differentiation, and maturation of newborn neurons into functional dentate granule cells, that integrate into the neural circuit and contribute to hippocampal function. Increasing evidence indicates that Wnt signaling regulates multiple aspects of adult hippocampal neurogenesis. Wnt ligands bind to Frizzled receptors and co-receptors to activate the canonical Wnt/β-catenin signaling pathway, or the non-canonical β-catenin-independent signaling cascades Wnt/Ca²⁺ and Wnt/planar cell polarity. Here, we summarize current knowledge on the roles of Wnt signaling components including ligands, receptors/co-receptors and soluble modulators in adult hippocampal neurogenesis. Also, we review the data suggesting distinctive roles for canonical and non-canonical Wnt signaling cascades in regulating different stages of neurogenesis. Finally, we discuss the evidence linking the dysfunction of Wnt signaling to the decline of neurogenesis observed in aging and Alzheimer's disease.

Keywords: Alzheimer’s disease; Wnt; adult neurogenesis; aging; hippocampus.

FIGURE 1

Stage-specific roles of Wnt signaling components in adult hippocampal neurogenesis. Schematic representation of the adult mouse hippocampus, and the stages of neurogenesis in the dentate gyrus. Type 1 NSCs proliferate asymmetrically to give rise to type 2 cells (types 2a and 2b), that differentiate into type 3 cells or neuroblast that develop into immature neurons, and ultimately into mature granule cells. The bottom panel indicates the temporal windows in which Wnt ligands, FZD receptors and co-receptors, Wnt signaling cascades and Wnt target genes have been involved (see text for details). DG, dentate gyrus; ML, molecular layer; GCL, granule cell layer; SGZ, subgranular zone.

FIGURE 2

Wnt signaling in the age-related decline in neurogenesis. A reduction in neurogenesis is observed in the dentate gyrus with age, which is accompanied by a decline in proliferation of neural precursor cells, a decreased dendritic development and delayed maturation of adult-born neurons. Evidence exists indicating that a decline in Wnt signaling is associated with this reduction of neurogenesis. In normal aging there is a decrease in the expression of most Wnt ligands in hippocampal astrocytes, a decrease in canonical Wnt signaling activity in the dentate gyrus, and a reduction in the expression of Wnt target genes that control neurogenesis (including Survivin and NeuroD1). Concomitantly, there is an increase in the expression of the Wnt inhibitors sFRP3 and Dkk1 in the hippocampus with age.

FIGURE 3

Genetic and pharmacological activation of Wnt/β-catenin promotes neurogenesis in the hippocampus of AD models. Schematic representation of the Wnt/β-catenin signaling pathway. Wnt ligand binds to FZD and LRP5/6, which trigger the recruitment of a multiprotein complex composed also of Axin, APC, CK1 and GSK-3β. This prevents the phosphorylation and degradation of β-catenin that translocates into the nucleus where it binds to members of the TCF/LEF families of transcription factors, to modulate the transcription of target genes. The Wnt/β-catenin signaling components that are target of genetic activation (Wnt3 and Wnt3a) and drugs able to stimulate neurogenesis in the hippocampus of animal models of AD are indicated. Red lines indicate inhibition; green lines indicate activation. Dotted red line indicates GSK-3β inactivation through the PI3K/Akt pathway; dotted green line indicates that the precise mechanism of activation of the Wnt/ β-catenin signaling remains elusive. Some of the drugs (see text for details) have shown to induce the expression of target genes involved in Wnt-mediated induction of proliferation (Cyclin D1) and differentiation (Ngn2 and NeuroD1) in adult hippocampal neurogenesis. VPA, valproic acid; Se-Met, Selenomethionine; ETH, Ethosuximide; XAN, Xanthoceraside.