Proliferation Of Hippocampal Progenitor Cells Research Articles

Hippocampal neurogenesis modulated by Quinic acid: A therapeutic strategy for the neurodegenerative disorders.

Neural progenitor cells (NPCs) reside in the brain and participate in the mechanism of neurogenesis that permits the brain to generate the building blocks for enhancement of cognitive abilities and acquisition of new skills. The existence of NPCs in brain has opened a novel dimension of research to explore their potential for treatment of various neurodegenerative disorders. The present study provides novel insights into the intracellular mechanisms in neuronal cells proliferation, maturation and differentiation regulated by Quinic acid (QA). Furthermore, this study might help in discovery and development of lead molecule that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using MTT assay. For that purpose, hippocampal cell cultures of neonatal rats were treated with different concentrations of QA and incubated for 24, 48 and 72 h. Gene and protein expressions of the selected molecular markers nestin, neuron-specific class III beta-tubulin (Tuj-1), neuronal nuclear protein (NeuN), neuronal differentiation 1 (NeuroD1), glial fibrillary acidic protein (GFAP), neuroligin (NLGN) and vimentin were analyzed. QA-induced cell proliferation and differentiation of hippocampal progenitor cells was also accompanied by significantly increased expression of progenitor and immature neuronal marker, mature neuronal marker and differentiating factor, that is, nestin, Tuj-1, NeuN and NeuroD1, respectively. On the other hand, vimentin downregulation and constant GFAP expression were observed following QA treatment. Additionally, the effects of QA on the recovery of stressed cells was studied using in vitro model of oxygen glucose deprivation (OGD). It was observed that hippocampal cells were able to recover from OGD following the treatment with QA. These findings suggest that QA treatment promotes hippocampal neurogenesis by proliferating and differentiating of NPCs and recovers neurons from stress caused by OGD. Thus, the neurogenic potential of QA can be explored for the treatment of neurodegenerative disorders.

Nanoemulsion-based piperine to enhance bioavailability for the treatment of LPS-induced depression-like behaviour in mice

In the present study, the objective was to encapsulate piperine in nanoform by solvent evaporation method and to investigate the antidepressant-like activity of nanopiperine in lipopolysaccharide (LPS) induced depression in mice. LPS-induced depression in mice was reversed by repeated treatment of nanopiperine at dosages of 5 and 10 mg/kg body weight for 14 days. After 24 h of LPS injection, the animals were exposed to a (TST) tail suspension test and (FST) forced swim test. A sequence of behaviours was measured on days 0, 7, and 14. On day 14, the animals were euthanized, and the blood was collected; biochemical analysis was performed for the measurement of inflammatory and oxidative stress markers. Within the same period, nanopiperine improved hippocampal progenitor cell proliferation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice subjected to LPS-induced stress. In addition, the neurotransmitter estimation by the HPLC method showed that nanopiperine increased the levels of neurotransmitters. In summary, the nanopiperine showed potent neuroprotective and antidepressant activity, and stability relating to the elevated level of hippocampal BDNF level and as compared to pure piperine, the nanopiperine showed better oral bioavailability and stability.

Zinc Water Prevents Autism-Like Behaviors in the BTBR Mice

This study aims to explore the effects of zinc water on autism-like behavior, convulsion threshold, and neurogenesis in ASD model animals. This study used the young BTBR ASD mouse model to explore the effect of a 6-week zinc water supplementation on ASD-like behaviors such as repetitive behavior and social communication disorder, seizure threshold, and the correlation with excitability regulation. The mice were divided into four groups of normal controls (B6) and models (BTBR) who did and did not receive zinc supplementation in water (B6, B6 + zinc, BTBR, and BTBR + zinc). For morphological changes in the hippocampus, we selected two indicators: hippocampal mossy fiber sprouting and neurogenesis. ASD-like behavior testing, seizure threshold determination, Timm staining, and neurogenesis-related assays—represented by Ki67 and DCX—were performed after 6 weeks of zinc supplementation. Our results show that zinc water can prevent autism-like behavior, reduce susceptibility to convulsions, and increase the proliferation of hippocampal progenitor cells in BTBR mice but has less effect on mossy fiber sprouting and neural progenitor cell differentiation. Zinc water reduces autism-like behavior in a partially inherited autism model mice—BTBR—which may be associated with hippocampal neural precursor cell proliferation and reversed hyperexcitability.

The metabolic regulator USF-1 is involved in the control of affective behaviour in mice

Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood. Here, we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF-1) knock-out (KO) mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits and found a reduction of depression-like and anxiety-like behaviours associated with USF-1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF-1 KO mice. Further, the absence of USF-1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNA-seq analysis characterised the molecular signature of USF-1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. The transcriptional changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity in USF-1 KO mice. Collectively these data suggest that the metabolic regulator USF-1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF-1-dependent BAT activation, but reflected in structural changes in the brain.

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model.

(1) The neurotrophic protein S100B is a marker of brain injury and has been associated with neuroregeneration. In S100Btg mice rendering 12 copies of the murine S100B gene we evaluated whether S100B may serve as a treatment option. (2) In juvenile, adult, and one-year-old S100Btg mice (female and male; n = 8 per group), progenitor cell proliferation was quantified in the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus with the proliferative marker Ki67 and BrdU (50 mg/kg). Concomitant signaling was quantified utilizing glial fibrillary acidic protein (GFAP), apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), and the receptor for advanced glycation end products (RAGE) immunohistochemistry. (3) Progenitor cell proliferation in the SGZ and migration to the GCL was enhanced. Hippocampal GFAP was reduced in one-year-old S100Btg mice. ApoE in the hippocampus and frontal cortex of male and BDNF in the frontal cortex of female S100Btg mice was reduced. RAGE was not affected. (4) Enhanced hippocampal neurogenesis in S100Btg mice was not accompanied by reactive astrogliosis. Sex- and brain region-specific variations of ApoE and BDNF require further elucidations. Our data reinforce the importance of this S100Btg model in evaluating the role of S100B in neuroregenerative medicine.

Neurobiological effects of phospholipids in vitro: Relevance to stress-related disorders

Nutrition is a crucial component for maintenance of brain function and mental health. Accumulating evidence suggests that certain molecular compounds derived from diet can exert neuroprotective effects against chronic stress, and moreover improve important neuronal processes vulnerable to the stress response, such as plasticity and neurogenesis. Phospholipids are naturally occurring amphipathic molecules with promising potential to promote brain health. However, it is unclear whether phospholipids are able to modulate neuronal function directly under a stress-related context. In this study, we investigate the neuroprotective effects of phosphatidylcholine (PC), lysophosphatidylcholine (LPC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylglycerol (PG), phosphatidic acid (PA), sphingomyelin (SM) and cardiolipin (CL) against corticosterone (CORT)-induced cytotoxicity in primary cultured rat cortical neurons. In addition, we examine their capacity to modulate proliferation and differentiation of hippocampal neural progenitor cells (NPCs).We show that PS, PG and PE can reverse CORT-induced cytotoxicity and neuronal depletion in cortical cells. On the other hand, phospholipid exposure was unable to prevent the decrease of Bdnf expression produced by CORT. Interestingly, PS was able to increase hippocampal NPCs neurosphere size, and PE elicited a significant increase in astrocytic differentiation in hippocampal NPCs. Together, these results indicate that specific phospholipids protect cortical cells against CORT-induced cytotoxicity and improve proliferation and astrocytic differentiation in hippocampal NPCs, suggesting potential implications on neurodevelopmental and neuroprotective pathways relevant for stress-related disorders.

MiR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells

MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.

Prolyl‐hydroxyproline, a collagen‐derived dipeptide, enhances hippocampal cell proliferation, which leads to antidepressant‐like effects in mice

Depression has been a mental health issue worldwide. We previously reported that ginger-degraded collagen hydrolysate (GDCH) suppressed depression-like behavior in mice. Furthermore, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG) were detected in the circulating blood after the oral administration of GDCH. In the present study, PO, but not OG, was detected in the cerebrospinal fluid of rats after the oral administration of GDCH, suggesting that PO is transported from blood to the brain. We then investigated the effects of PO and OG on the depression-like behavior of mice. The oral administration of PO significantly decreased depression-like behavior in the forced swim test. OG had no antidepressant-like effect. In addition, proline and hydroxyproline, components of PO, also had no antidepressant-like effect after their oral administration. PO significantly increased the gene expression of brain-derived neurotrophic factor and nerve growth factor in the hippocampus, and promoted the proliferation of neural progenitor cells in vivo and in vitro. PO also increased the dopamine concentration in the prefrontal cortex. Thus, PO-dependent regulation of neurotrophic function and neurotransmitter may be the mechanism for antidepressant-like behavior. Together, these results demonstrate that PO is an antidepressant bioactive peptide accompanying the proliferation of hippocampal neural progenitor cells.

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Depression is a worldwide health problem. In the present study, we found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), administered orally, intracerebroventricularly, or intraperitoneally exhibited a potent antidepressant-like activity in the forced swim and tail suspension tests in naïve mice. YL increased the amount of cells expressing c-Fos, a marker for neuronal activity, in the dentate gyrus of the hippocampus. YL increased bromo-2′-deoxyuridine-positive cells and doublecortin expression in the dentate gyrus of the hippocampus, suggesting that YL enhanced the proliferation of hippocampal progenitor cells in vivo and in vitro. YL did not affect hippocampal mRNA and protein expression of BDNF, which is a regulatory factor of both neurogenesis and depression-like behavior. Intriguingly, YL suppressed activation of the hypothalamo-pituitary-adrenal axis by forced swim stress. Moreover, other aromatic amino acid-leucines, Phe-Leu and Trp-Leu, also exhibited antidepressant-like activities, suggesting that the structure of aromatic amino acid-leucine may be important for antidepressant activity. In addition, bovine milk casein-derived peptide, Tyr-Leu-Gly (YLG), an anxiolytic peptide, exhibited an antidepressant-like activity. Our findings demonstrate that YL exhibits an antidepressant-like effect, moderates the stress response, and induces hippocampal neuronal proliferation through a signal pathway independent of BDNF.

The potential oncogenic role of the RAS-like GTP-binding gene RIT1 in glioblastoma.

Glioblastoma is the most common type of malignant brain tumors and the most feared cancer among adults. The poor prognosis among patients affected with this type of cancer is associated with its high-invasiveness and the lack of successful therapies. A comprehensive understanding for the early molecular mechanisms in glioblastoma would definitely enhance the diagnosis and the treatment strategies. Deregulated expression of key genes that are known to be involved in early neurogenesis could be the instigator of brain tumorigenesis. Ras Like Without CAAX 1 (RIT1) gene that encodes an unusual "orphan" GTPase protein belongs to this category of critical genes that are known to be involved in controlling sequential proliferation and differentiation of adult hippocampal neural progenitor cells. In this study, we surveyed RIT1 gene expression by in-silico approaches to determine its spatio-temporal pattern in glioblastoma. Our results revealed a significant and progressive upregulation of RIT1 mRNA levels in various publicly available datasets. RIT1 expression ranked among the top upregulated genes in glioblastoma cohorts and it correlated with poor overall survival. Genetic and epigenetic analysis of RIT1 didn't reveal any significant aberration that could underlie its deregulated expression. Yet, our results highlighted the possibility of its activity to be transcriptionally controlled by STAT3, one of the main players in the onset of glioblastoma. In conclusion, our study presented for the first time a potential oncogenic role for RIT1 in glioblastoma. Knowing that the RAS superfamily of proteins has created an evolution in the cancer field, RIT1 should be added to this list through further investigations on its possible usage as a biomarker and therapeutic target in glioblastoma.

Treatment with the Neurotrophic Protein S100B Increases Synaptogenesis after Traumatic Brain Injury.

Release of neurotrophic and growth factors such as S100 calcium-binding protein B (S100B) yields an endogenous repair mechanism following traumatic brain injury (TBI). Although nanomolar S100B concentrations enhance hippocampal progenitor cell proliferation, neuronal differentiation, and cognitive recovery, micromolar concentrations may foster inflammatory effects counteracting neuroplasticity. The purpose of the present study was to investigate the effect of S100B on synaptogenesis and microglial activation following experimental TBI. Male Sprague-Dawley rats (n = 40) were subjected to lateral fluid percussion or sham injury, and S100B (50 ng/h) or phosphate buffered saline (PBS) was infused into the lateral ventricle for 7 days using osmotic micropumps. The animals were euthanized on day 5 or, 5 weeks post-injury, and 5 μm sections, 100 μm apart (bregma -3.3 to -5.6mm) were analyzed histologically. Cell proliferation was assessed injecting the mitotic marker Bromodeoxyuridine (BrdU) on day 2. S100B enhanced significantly the synaptophysin (SYN) expression and microglial activation (ectodysplasin [ED1]) in the hippocampus in TBI and uninjured sham animals. The glial activation (glial fibrillary acidic protein [GFAP], S100B immunoreactive cells), axonal injury (APP) and cell death (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) were not altered. Triple-labelling with BrdU, NeuN, and SYN confirmed a significant participation of S100B in hippocampal synaptogenesis in TBI and uninjured sham animals. Our results demonstrate that S100B augments hippocampal neuro- and synaptogenesis in TBI and uninjured sham animals, thereby improving cognitive function as demonstrated earlier. The S100B-induced microglial activation does not counteract this effect within the first 5weeks. Further studies are required to elucidate respective cellular signaling mechanisms and possible long-term effects.

Intranigral Injection of Endotoxin Suppresses Proliferation of Hippocampal Progenitor Cells.

Brain inflammation can result in functional disorders observed in several neurodegenerative diseases and that can be also associated with reduced neurogenesis. In this study, we investigate the effect of mild inflammation, induced by unilateral injection of Endotoxin (ET) in the substantia nigra (SN)/Ventral Tegmental Area, on the proliferation and survival of stem/progenitor cells in the dentate gyrus (DG) of the hippocampus. Adult female rats received unilateral injection of ET (2 μg/2 μl saline) or sterile saline (2 μl) in the right SN followed by 5′-Bromo-2′-deoxyuridine (BrdU) injections (66 mg/kg/injection). Intranigral ET injection induced bilateral decrease in the number of newly born BrdU positive cells in the DG. This effect was paralleled by a significant decrease in the exploratory behavior of rats, as assessed by the Y-maze novel arm exploration task. ET also induced a transient decrease in the number of tyrosine hydroxylase-positive cells in the injected SN, impaired motor behavior, and caused microglial activation in the SN. This study provides an experimental simulation of the remote effects of moderate and reversible neuroinflammation resulting in impaired communication between midbrain dopaminergic neurons and the hippocampus.

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHNPCs) and in a non-cell autonomous manner. These findings were confirmed in PS1M146V/+ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1M146V/+ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1M146V/+ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.SIGNIFICANCE STATEMENT Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD). Mutant PS1 expression enhances the levels and assembly of toxic Aβ42 peptides and impairs the self-renewal and neuronal differentiation of adult hippocampal neural progenitor cells (AHNPCs) following environmental enrichment (EE) that is associated with heightened baseline anxiety. We now show that microglial depletion fully restores the EE-mediated impairments in AHNPC phenotypes and suppresses the heightened baseline anxiety observed in mice expressing FAD-linked PS1. Thus, we conclude that the memory deficits and anxiety-related behaviors in patients with PS1 mutations is a reflection not just of an increase in the levels of Aβ42 peptides, but to impairments in the self-renewal and neuronal differentiation of AHNPCs that modulate affective behaviors.

Sleep deprivation inhibits proliferation of adult hippocampal neural progenitor cells by a mechanism involving IL-17 and p38 MAPK

Sleep deprivation impairs hippocampal neurogenesis, but the underlying mechanisms are inadequately understood. Sleep deprivation is associated with an increased production of pro-inflammatory factors. In this study, we demonstrate that acute rapid eye movement (REM) sleep deprivation in mice for 3 days leads to increased expression of interleukin (IL)-17A, IL-17F and activation of p38 MAPK pathway in the hippocampus, together with suppressed cell proliferation in the dentate gyrus. Similarly, activation of p38 MAPK and suppressed cell proliferation in the dentate gyrus were observed after administration of recombinant IL-17 in mice without sleep deprivation. Pharmacological blockade of the p38 MAPK after sleep deprivation mitigates sleep deprivation-induced ablation of cell proliferation in the dentate gyrus with unaltered expression of IL-17A and IL-17F. In addition, hippocampal neural progenitor cells express IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC). These findings suggest that acute REM sleep deprivation suppresses proliferation of adult hippocampal neural progenitor cells by a mechanism involving IL-17 and p38 MAPK signaling.

Postnatal administration of memantine rescues TNF-α-induced decreased hippocampal precursor proliferation

Pro-inflammatory cytokine exposure in early postnatal life triggers clear neurotoxic effects on the developing hippocampus. Tumor necrosis factor alpha (TNF-α) is one of the inflammatory mediators and is a potent inhibitor of neurogenesis. Memantine (MEM) is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been demonstrated to increase the proliferation of hippocampal progenitor cells. However, the effects of MEM on TNF-α-mediated impairment of hippocampal precursor proliferation remain unclear. In this study, mice were exposed to TNF-α and later treated with MEM to evaluate its protective effects on TNF-α-mediated toxicity during hippocampal development. The results indicated that brief exposure to TNF-α on postnatal days 3 and 5 resulted in a significant impairment of hippocampal precursor proliferation and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by MEM treatment. We further confirmed that MEM treatment reversed the TNF-α-induced microglia activation and up-regulation of hippocampal NF-κB, MCP-1 and IL-6 mRNA levels, which may be related to the proliferation and maintenance of NPCs. Overall, our results suggest that MEM treatment protects against TNF-α-induced repression of hippocampal precursor proliferation in postnatal mice by partially attenuating neuroinflammatory responses.

Agmatine inhibits chronic morphine exposure-induced impairment of hippocampal neural progenitor proliferation in adult rats

Our previous studies have shown that agmatine inhibited opioid dependence, yet the neural mechanism remains unclear. Growing evidence showed that opioids decrease neurogenesis in the adult hippocampal subgranular zone by inhibiting neural progenitor proliferation. However, whether agmatine affects chronic opioid exposure-induced impairment to hippocampal neural progenitor cell proliferation remains unknown. In the present study, we investigated the role of agmatine in hippocampal neural progenitors in morphine dependence rats. We found that chronic administration of morphine for 12 days induced morphine dependence in rats. This treatment not only decreased the proliferation of hippocampal neural progenitors in the granule cell layer, but also decreased the levels of hippocampal cAMP, pCREB and BDNF. However, these alterations can be restored to normal levels by co-treatment of agmatine (10mg/kg, s.c.). In vitro treatment with agmatine (10µM) for two days significantly increased proliferation of the cultured hippocampal neural progenitors. Concurrent treatment of agmatine (10µM) with morphine (10 or 50µM) reversed the supression of morphine-induced neural progenitor proliferation. In conclusion, we found that agmatine abolished chronic morphine-induced decrease in proliferation of hippocampal progenitors in vivo and in vitro, which may be due to the increase in cAMP-CREB-BDNF signaling. The enhancement of agmatine to proliferation of hippocampal progenitors may be one of the important mechanisms involved in the inhibition of morphine dependence by agmatine.

RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis

Adult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease

We previously showed that gintonin, an exogenous lysophosphatidic acid (LPA) receptor ligand, attenuated β-amyloid plaque formation in the cortex and hippocampus, and restored β-amyloid-induced memory dysfunction. Both endogenous LPA and LPA receptors play a key role in embryonic brain development. However, little is known about whether gintonin can induce hippocampal cell proliferation in adult wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease (AD). In the present study, we examined the effects of gintonin on the proliferation of hippocampal neural progenitor cells (NPCs) in vitro and its effects on the hippocampal cell proliferation in wild-type mice and a transgenic AD mouse model. Gintonin treatment increased 5-bromo-2'-deoxyuridine (BrdU) incorporation in hippocampal NPCs in a dose- and time-dependent manner. Gintonin (0.3 μg/ml) increased the immunostaining of glial fibrillary acidic protein, NeuN, and LPA1 receptor in hippocampal NPCs. However, the gintonin-induced increase in BrdU incorporation and immunostaining of biomarkers was blocked by an LPA1/3 receptor antagonist and Ca2+ chelator. Oral administration of the gintonin-enriched fraction (50 and 100 mg/kg) increased hippocampal BrdU incorporation and LPA1/3 receptor expression in adult wild-type and transgenic AD mice. The present study showed that gintonin could increase the number of hippocampal neurons in adult wild-type mice and a transgenic AD mouse model. Our results indicate that gintonin-mediated hippocampal cell proliferation contributes to the gintonin-mediated restorative effect against β-amyloid-induced hippocampal dysfunction. These results support the use of gintonin for the prevention or treatment of neurodegenerative diseases such as AD via promotion of hippocampal neurogenesis.

An 18-mer Peptide Derived from Prosaposin Ameliorates the Effects of Aβ1-42 Neurotoxicity on Hippocampal Neurogenesis and Memory Deficit in Mice.

The pathological hallmarks of Alzheimer's disease (AD) include amyloid-β (Aβ) accumulation, neurofibrillary tangle formation, synaptic dysfunction, and neuronal loss. The present study was performed to investigate the protective effects and mechanism of action of a prosaposin-derived 18-mer peptide (PS18: LSELIINNATEELLIKGL) on mice hippocampal progenitor cell proliferation, neurogenesis, and memory tasks after intracerebroventricular injection of Aβ1-42 peptide. Seven days after Aβ1-42 injection, significant proliferation of hippocampal progenitor cells and memory impairment were evident. Two weeks after Aβ1-42 peptide injection, elevated numbers of surviving 5-bromo-2-deoxyuridine cells and newly formed neurons were detected. Treatment with PS18 attenuated these effects evoked by Aβ1-42. Our data indicate that treatment with PS18 partially attenuated the increase in hippocampal neurogenesis caused by Aβ1-42-induced neuroinflammation and prevented memory deficits associated with increased numbers of activated glial cells. We observed an increase in ADAM10 and decreases in BACE1, PS1/2, and AβPP protein levels, suggesting that PS18 enhances the nonamyloidogenic AβPP cleavage pathway. Importantly, our results further showed that PS18 activated the PI3K/Akt pathway, phosphorylated GSK-3α/β, and, as a consequence, exerted a neuroprotective effect. In addition, PS18 showed a protective effect against Aβ1-42-induced neurotoxicity via suppression of the caspase pathway; upregulation of Bcl-2; downregulation of BAX, attenuating mitochondrial damage; and inhibition of caspase-3. These findings suggest that PS18 may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases, such as AD.

The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors.

Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases.