Abstract
Wnt signaling has been implicated in Alzheimer’s disease (AD) pathogenesis, but no studies have described Wnt signaling in aging brain. Phosphorylation of the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (Lrp6), is a sensitive indicator of Wnt ligand-receptor interaction and canonical Wnt signaling. We report that in aged human temporal lobe, the phospho-Lrp6 (pLrp6) epitope localizes to neurons in the entorhinal cortex (EC), the dentate gyrus (DG), and the hippocampal formation, especially in the CA3 field. Activated Lrp6 is detected in neuronal soma and in neuronal processes, particularly in the mossy fiber terminals in the stratum lucidum of CA3. These three regions and their connectivity represent the afferent arm of the major hippocampal circuit. In the DG, cells positive for pLrp6 include Type 1 and Type 2 hippocampal progenitor cells. Overall, these data indicate regional Wnt receptor activation in the human hippocampus that is most prominent in the cells comprising the afferent arm of the major hippocampal circuit that is associated with learning and memory functions. These findings are consistent with data from rodent studies which suggest an important role for Wnts in adult neurogenesis in the human DG. We speculate that Wnt signaling may be an activity-dependent trophic influence in the hippocampus.
Highlights
Limited human data suggest that adult neurogenesis in the human hippocampus may differ substantially from rodent models
We demonstrate that pLrp6 is present in post mortem aged human brain and we report three novel findings
These results establish a method for studying Wnt signaling activity in situ, demonstrate regional Wnt signaling within the medial temporal lobe structures, and implicate Wnt signaling in adult neurogenesis in human brain
Summary
Limited human data suggest that adult neurogenesis in the human hippocampus may differ substantially from rodent models. We report that Wnt receptor activation, as indicated by the presence of the pLrp epitope, is abundant in cells in the CA3 field, DG and EC of adult human hippocampus. These cells comprise the afferent arm of the major circuit of the hippocampus that is critical for memory and learning [10]. We find that pLrp6positive cells in the aged human dentate gyrus bear markers of hippocampal progenitor cells and mature neurons These findings are consistent with rodent data and suggest that Wnt signaling is active in neurons in the adult human hippocampus
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