Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis

M Okamoto, K Inoue, H Iwamura… - The FASEB …, 2011 - Wiley Online Library
M Okamoto, K Inoue, H Iwamura, K Terashima, H Soya, M Asashima, T Kuwabara
The FASEB Journal, 2011Wiley Online Library
The mammalian brain contains neural stem cells (NSCs) that enable continued
neurogenesis throughout adulthood. However, NSC function and/or numbers decline with
increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3
promote NSC differentiation in a paracrine manner. Here, we show that both the levels of
Wnt3 protein and the number of Wnt3‐secreting astrocytes influence the impairment of adult
neurogenesis during aging. The age‐associated reduction in Wnt3 levels affects the …
Abstract
The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner. Here, we show that both the levels of Wnt3 protein and the number of Wnt3‐secreting astrocytes influence the impairment of adult neurogenesis during aging. The age‐associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age‐ or stimulus‐associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.—Okamoto, M., Inoue, K., Iwamura, H., Terashima, K., Soya, H., Asashima, M., Kuwabara, T. Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J. 25, 3570–3582 (2011). www.fasebj.org
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