Aging brain microenvironment decreases hippocampal neurogenesis through Wnt‐mediated survivin signaling

Abstract

Summary Accumulating evidence suggests that adult hippocampus neurogenesis relies on the controlled and continued proliferation of neural progenitor cells (NPCs). With age, neurogenesis decreases through mechanisms that remain unclear, but are believed to involve changes in the NPC microenvironment. Here we provide evidence that NPC proliferation in the adult brain is in part regulated by astrocytes via Wnt signaling and that this cellular cross-talk is modified in the aging brain, leading to decreased proliferation of NPCs. Furthermore, we show that astrocytes regulate the NPC cell cycle by acting on the expression levels of survivin, a known mitotic regulator. Among cell cycle genes found downregulated in aged NPCs, survivin was the only one that restored NPC proliferation in the aged brain. Our results provide a mechanism for the gradual loss of neurogenesis in the brain associated with aging and suggest that targeted modulation of survivin expression directly or through Wnt-signaling could be used to stimulate adult neurogenesis.

Nanoformulated cell-penetrating survivin mutant and its dual actions

“…Supporting this concept, one study observed that introduction of survivin restored neural progenitor cell proliferation in the brain, which was achieved by the modulating survivin expression or Wnt signaling. 61 The neuroprotective activity of survivin was also confirmed in an in vitro model of multiple sclerosis, where mouse brain astrocytes were insulted with the BeAn strain of Theiler murine encephalomyelitis virus. Interesting results were reported with the upregulation of survivin expression, where it formed a complex with the caspase-3 enzyme, nullifying the apoptotic events to be followed.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…The phenotype of Wnt-3a mutant mice (Table 1) property that is lost in ageing mice [56,124]. Further evidence that Wnt-mediated neurogenesis contributes to adult hippocampal function comes from studies in which lentiviral expression of a dominant-negative form of Wnt-1 (dnWnt-1) was found to reduce neurogenesis, resulting in impaired long-term retention of spatial and object recognition memory [56,57].…”

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…7 However, aging decreases neurogenesis in the mammalian brain due to an increase in negative regulators of neurogenesis. [8][9][10][11] For instance, Wnt production was shown to decline with aging, which in turn decreases NSC proliferation. 11 One might suppose that cerebral damage would lead to a molecular and cellular imbalance in the neurovascular niche favoring negative regulators and thus impair endogenous neurogenesis.…”

“…[8][9][10][11] For instance, Wnt production was shown to decline with aging, which in turn decreases NSC proliferation. 11 One might suppose that cerebral damage would lead to a molecular and cellular imbalance in the neurovascular niche favoring negative regulators and thus impair endogenous neurogenesis. However, studies in rodents provide accumulating evidence that the neurogenic capacity is preserved or even increases after injurious events such as seizures, 12 stroke, 13 or hypoxia-ischemia (HI).…”