Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis

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.

Active Expression of Retroelements in Neurons Differentiated from Adult Hippocampal Neural Stem Cells

“…Differentiation into the astrocyte lineage was stimulated by the addition of 50 ng/mL leukemia inhibitory factor (LIF) and 50 ng/mL bone morphogenetic protein 2 (BMP2). Astrocytes prepared in vitro expressed Wnt3 factors, consistent with in vivo data (Lie et al, 2005;Kuwabara et al, 2009;Okamoto et al, 2011).…”

When stem cells grow old: phenotypes and mechanisms of stem cell aging

“…Unlike other stem cells, however, the in vitro function of aged NSCs on a per-cell basis is not substantially impaired with age (Ahlenius et al, 2009), which implies that cell-extrinsic factors are largely at play. Indeed, heterochronic parabiosis (the joining of the circulatory systems of two animals of different age) and restoring the levels of IGF-1, GH, Wnt3, TGF-β or GDF11 in old mice to those found in young mice improves neurogenesis (Blackmore et al, 2009;Katsimpardi et al, 2014;Lichtenwalner et al, 2001;Okamoto et al, 2011;Pineda et al, 2013;Villeda et al, 2014). An age-dependent change in the senescence of NSCs also contributes to their declining numbers (Molofsky et al, 2006;Nishino et al, 2008) and might underlie learning and memory deficits in the elderly (Zhao et al, 2008a).…”

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging

“…Increasing evidence supports the idea that, during aging, WNT signaling has an instructive role in neuronal fate determination from neural progenitors (2). For example, WNT3 expression decreases during aging (3), while levels of the WNT antagonist Dickkopf 1 (DKK1) increase specifically in the hippocampus (4). It remains unclear whether WNT plays any role in the SVZ; if it does, the mechanism for its regulation during aging is largely unknown.…”