Introduction
Since the first report of continual production of new neurons in the adult hippocampus (Altman and Das, 1965), a large number of investigations have characterized a wide range of biological properties of adult hippocampal neurogenesis from its intrinsic biology to functional implications. Several lines of evidence have suggested that adult hippocampal neurogenesis is important in psychiatric and neurological disorders, including addiction, depression, epilepsy, schizophrenia, and cognitive function (DeCarolis and Eisch, 2010, Chambers, 2013, Rotheneichner et al., 2013, Mahar et al., 2014, Na et al., 2014). Although current findings in this field suggest that adult hippocampal neurogenesis is neither the sole cause of such illnesses nor the sole mechanism of treatment efficacy, it is likely an important contributor to these complex disorders. For example, a growing body of evidence supports the view that promotion of adult hippocampal neurogenesis improves pattern separation and spatial memory (Sahay et al., 2011, Stone et al., 2011, Song et al., 2013). Recent evidence has suggested that downregulation of neurogenesis in the Alzheimer’s disease mouse model brain can be rescued by physical exercise or exposure to environmental enrichment, a putative positive regulator of adult neurogenesis (Lazarov et al., 2010, Intlekofer and Cotman, 2013, Li et al., 2014), and cognitive performance may also be improved by such stimuli (Rodgers et al., 2013, Li et al., 2014).
Thymosin β4 (TB4), the most abundant member of the thymosin β family, is a major actin-sequestering peptide that is widely distributed in mammalian tissues, including the nervous system (Low and Goldstein, 1982, Hannappel and van Kampen, 1987, Huff et al., 2001b, Paulussen and Arckens, 2012). The functional activity of TB4 is to inhibit organization of the actin cytoskeleton by sequestration of G-actin monomers, thereby enabling cells to migrate (Goldstein et al., 2005). In the central nervous system, TB4 mediates neuroprotection (Morris et al., 2010a, Morris et al., 2010b, Xiong et al., 2012a, Xiong et al., 2012b) and has been proposed to regulate normal patterns of neurite outgrowth (Roth et al., 1999, van Kesteren et al., 2006), a process that is highly dependent on the reorganization and dynamics of the actin cytoskeleton (Chen et al., 2000, Gallo and Letourneau, 2004). Moreover, the presence of this peptide in the nervous system likely plays a role in synaptogenesis, axon growth, cell migration, and plastic changes in dendritic spines (Fifkova, 1985, Border et al., 1993, Otero et al., 1993, Huff et al., 2001b, Morris et al., 2010b). Interestingly, as a peptide fragment of TB4, N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP) showed angiogenic effect in vivo and in vitro as like TB4 (Liu et al., blood 2003). Ac-SDKP had lower molecular weight than full length TB4. Moreover, based on previous reports (Defard et al., 1997, Zuo et al., 2013), Ac-SDKP seems to exert similar effects with TB4 in some aspects. Therefore, we are interested in the effect of Ac-SDKP on brain functions.
Previous study has shown that neurons derived from TB4-antisense-transduced neural progenitor cells (NPCs) promote the functional recovery of spinal cord injury mouse model suggesting implications of TB4 in neuronal differentiation (Mollinari et al., 2009a). Moreover, in a traumatic brain injury model, systemic TB4 administration protected brain injury and increased angiogenesis and neurogenesis (Xiong et al., 2012a, Xiong et al., 2012b). Taken together, it can be speculated that TB4 regulates NPC cell fate. However, the effect of Ac-SDKP in neurogenesis is not yet studied. Therefore, we aimed to elucidate the effect of Ac-SDKP in neural proliferation, survival, and we found that Ac-SDKP increases newborn neurons in the hippocampus through VEGF signaling.
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Animals
Male C57BL/6J mice (25–28 g, 8 weeks) were purchased from the Orient Co., Ltd, which is a branch of the Charles River Laboratories (Gyungi-do, Korea). Animals were housed four or five per cage and allowed access to water and food ad libitum. The cages were maintained at a constant temperature (23 ± 1 °C) and relative humidity (60 ± 10%) under a 12-h light/dark cycle (lights on from 07:30 to 19:30). All the experimental protocols using animals were approved by the Institutional Animal Care and Use
Ac-SDKP facilitates neural cell proliferation
We tested the effect of a transient increase in TB4 signaling on hippocampal neural proliferation and neurogenesis using a functional fragment of TB4, Ac-SDKP (Grillon et al., 1990, Rieger et al., 1993, Huff et al., 2001a). To examine the effect of Ac-SDKP on neural cell proliferation in the hippocampus, we first tested the effect of SC peptide on neurogenesis. And we found that the number of BrdU-positive cells are similar between saline and SC peptide groups. Next, Ac-SDKP or SC peptide was
Discussion
A number of different signaling molecules, including a variety of protein kinases, have been identified as being involved in adult neurogenesis. For the first time, we showed that β-thymosin peptide active fragment, Ac-SDKP, could increase adult neurogenesis, which may be highly relevant in preventing various neurodegenerative diseases by the replenishment of damaged neurons. Consistently, the pathways activated in Ac-SDKP treatment were similar to those activated in TB4 treatment (Huang et
Competing financial interests
The authors declare no competing financial interests.
Acknowledgments
This work was supported by the National Research Foundation of South Korea (NRF) grant funded by the Korea government (MSIP) (2015R1A2A2A01007838 and #2010-0018545).
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These authors equally contributed to this work.
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