Loss of Dickopf-1 restores neurogenesis and memory in animal model
medwireNews: Loss of the molecule Dickopf-1 (Dkk1) in the hippocampus in older animals increases neurogenesis, research shows.
The loss of Dkk1 also increased activity of signaling pathways in neural progenitor cells, leading to self-renewal and survival of the neural progenitor cells. This suggests that Dkk1 is a molecule that accumulates with age and inhibits the formation of new neurons.
In blocking the production of Dkk1 in aged mice, "we released a brake on neuronal birth, thereby resetting performance in spatial memory tasks back to levels observed in younger animals," said study author Ana Martin-Villalba (German Cancer Research Center, Heidelberg) in a press release accompanying the paper, published in Cell Stem Cell.
Memory impairment in older adults has been shown to be associated with the age-related decline in hippocampal neurogenesis. The researchers explain that neurogenesis takes place in the subventricular and the subgranular zones (SGZ) of the hippocampus. The SGZ regulates the maintenance, activation, and fate of neural progenitor cells through various signaling molecules, including Wnt signaling.
The researchers examined neurogenesis in very old mutant mice lacking the expression of Dkk1. They found that in these 2-year-old Nestin-Dkk1 mice, the number of newborn neurons was 80% higher than in age-matched counterparts.
Experiments also showed that neural progenitor cells with an induced loss of Dkk1 increased Wnt activity, and this led to enhanced self-renewal and increased generation of immature neurons.
In tests of working memory, increased neurogenesis observed in Nestin-Dkk1 mice resulted in improved performance on spatial working memory tasks and memory consolidation. These mice also showed improvements in affective behavior.
In the hippocampus of older mice, Dkk1 mRNA and protein expression was significantly higher than in younger mice. The observed increase in Dkk1 expression could be one reason for the age-related decay in neural progenitor cell (NPC) self-renewal, say the researchers.
"Thus, if loss of Dkk1 increases the self-renewals on NPCs in vivo, then loss of Dkk1 would lead to the maintenance of neurogenesis in old age," explain Martin-Villalba and colleagues.
The authors conclude that "the contribution of newly generated young neurons to memory and affective behavior opens tantalizing opportunities for the prevention of affective impairments and age-related cognitive decline."
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