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Factors That Influence Adult Neurogenesis as Potential Therapy

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Review

Factors That Influence Adult Neurogenesis as Potential Therapy

Belal Shohayeb et al. Transl Neurodegener.

Abstract

Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain. This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain. The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders. In addition, adult neurogenesis might also play a role in mood and affective disorders. The factors that regulate adult neurogenesis have been broadly studied. However, the underlying molecular mechanisms of regulating neurogenesis are still not fully defined. In this review, we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis. We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration.

Keywords: Cytokines; Extrinsic factors; Neurotrophins; Niche; Stem cells; Therapy; Transcription factors.

Conflict of interest statement

not applicablenot applicable“The authors declare that they have no competing interests”

Figures

Fig. 1
Fig. 1
Adult neurogenic niche. Cross section of the adult brain showing regions of SGZ and SVZ, where neurogenesis takes place. The schematic illustrates neurogenesis involving NSCs development into mature neurons and the neurogenic niches of Blood Vessels (BV), astrocytes and cilia, as well as transcription programs in the SGZ (a) and SVZ (b). Neuronal migration from the SVZ to the OB via the RMS is also shown in (b)
Fig. 2
Fig. 2
Factors upregulating neurotrophins. BDNF levels and consequently initiate NSC proliferation via activation of the TrkB receptor, which later differentiates into dopaminergic neurons (a). NGF, through its downstream receptor TrkA, initiates NSC proliferation that results in cholinergic neurons formation (b). The dopaminergic and cholinergic neuronal differentiation occurs primarily during developmental neurogenesis, however, environmental factors, stem cell transplantation, and anti-inflammatory drugs could potentially induce these processes in adult neurogenesis
Fig. 3
Fig. 3
Influence of Notch and WNT signaling on neurogenesis. Wnt signaling enhances NSCs differentiation through the transcriptional upregulation of NeuroD1 and inhibiting Sox2 from restraining NeuroD1 expression. Upon aging WIP1 is downregulated and allow DKK3 to inhibit Wnt signaling that results in reduced NeuroD1 levels and NSC differentiation. In contrast, Sox2, downstream Notch signaling, enhances NSC proliferation. TLX alters the expression of cell cycle regulators as pten, p57, and p21 and induces NSC proliferation
Fig. 4
Fig. 4
Microglia and neurogenesis modulation. Microglia at the normal state is more likely to undergo neurogenesis rather than gliogenesis (a). Upon microglia activation by stress factors such as aging or injury, pro-inflammatory cytokines are released and enhance gliogenesis at the expense of neurogenesis (b). In the next stage, microglia reach an immunomodulatory state where anti-inflammatory cytokines are released and a preference for neurogenesis is returned (c). ‘A’ - Astrocyte, ‘O’ - Oligodendrocyte, ‘N’ - Neuron

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