Many genes in the human genome encode proteins that are dosage sensitive, meaning they require protein levels within a narrow range to properly execute function. To investigate if clinically relevant variation in protein levels impacts the same downstream pathways in human disease, we generated cell models of two SETBP1 syndromes: Schinzel-Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disease (SHD), where SGS is caused by too much protein, and SHD is caused by not enough SETBP1. Using patient and sex-matched healthy first-degree relatives from both SGS and SHD SETBP1 cases, we assessed how SETBP1 protein dosage affects downstream pathways in human forebrain progenitor cells. We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental. We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope. SETBP1 protein doses may exert significant influence on global gene expression patterns via these SETBP1 nuclear bodies. This work provides evidence for the importance of SETBP1 protein dose in human brain development, with implications for two neurodevelopmental disorders.

Alzheimer's disease (AD) is a progressively worsening neurodegenerative disorder characterized primarily by the deposition of amyloid beta (Aβ) plaques in the brain and the abnormal aggregation of tau protein forming neurofibrillary tangles. These pathological changes lead to impaired neuronal function and cell death, subsequently affecting the structure and function of the brain. Fibroblast growth factors (FGFs) are a group of proteins that play crucial roles in various biological processes, including cell proliferation, differentiation, and survival. This article reviews the expression and regulation of FGFs in the central nervous system and how they affect neuronal survival, as well as the changes in FGF signaling pathways and its regulation of programmed cell death in AD. It particularly focuses on the impact of FGF1, FGF2, FGF21, other members of the FGF family, and FGFR on the pathophysiological mechanisms of AD. The potential of the PI3K/AKT/GSK-3β, Wnt/β-catenin, and NF-κB signaling pathways as targets for AD treatment is also discussed. Furthermore, the relationship between FGF-regulated ferroptosis, Pyroptosis and Autophagy and AD is explored, along with the role of these mechanisms in improving the progression of AD.

Adult neurogenesis in the hippocampus, involving the generation and integration of new neurons, is essential for behavioral pattern separation, which supports accurate memory recall and cognitive plasticity. Here, we explore the role of the DNA repair protein NEIL3 in adult hippocampal neurogenesis and behavioral pattern separation. NEIL3 is required for efficient proliferation and neuronal differentiation of neonatal NSPCs and adult-born NPCs in the hippocampus following a behavioral pattern separation task. NEIL3-depleted mice exhibited a reduced preference for the novel object location, indicating a deficit in pattern separation. NEIL3-deficient adult-born neurons exhibited a significant reduction in mature-like membrane properties, indicating impaired functional maturation. Interestingly, these impairments were not associated with the decreased genomic integrity but with the altered transcriptional regulation of the Wnt signaling pathway. Given the importance of adult neurogenesis in cognitive function, targeting NEIL3 could offer therapeutic potential for addressing age-related hippocampal dysfunction and cognitive decline.

Hippocampal neurogenesis, the generation of new neurons in the dentate gyrus (DG) of mammalian hippocampus, is essential for cognitive and emotional processes. Despite advances in understanding the transcription factors and signaling pathways that regulate DG neurogenesis, the epigenetic mechanisms underlying the molecular changes necessary for granule neuron generation remain poorly understood. In this study, we investigate the role of the H3K9 demethylase KDM3A in postnatal neurogenesis in mouse DG. Using Kdm3a-tdTomato reporter mice, we demonstrate that KDM3A is predominantly expressed in neural stem/progenitor cells (NSPCs) during postnatal DG development. Conventional or conditional knockout (cKO) of Kdm3a in NSPCs hinders postnatal neurogenesis, compromising learning and memory abilities and impairing brain injury repair in mice. Loss of KDM3A in NSPCs suppresses proliferation and neuronal differentiation while promoting glial differentiation in vitro. KDM3A localizes both in the nucleus and cytoplasm of NSPCs and regulates the Wnt/β-catenin signaling pathway through dual mechanisms. Firstly, KDM3A modulates the transcription of Wnt targets and a set of neurogenesis-related genes through its histone demethylase activity. Secondly, in the cytoplasm, KDM3A interacts with casein kinase I alpha (CK1α), regulating its ubiquitination. Loss of KDM3A enhances CK1α stability, leading to increased phosphorylation and degradation of β-catenin. Finally, quercetin, a geroprotective small molecule, upregulates KDM3A protein expression and promotes adult hippocampal neurogenesis following brain injury. However, these effects are diminished in Kdm3a KO mice, indicating that quercetin primarily promotes hippocampal neurogenesis through the regulation of KDM3A. In conclusion, our study highlights KDM3A as a crucial regulator of postnatal hippocampal neurogenesis, influencing NSPC proliferation and differentiation via the Wnt/β-catenin signaling pathway. These findings have potential implications for the development of new therapeutic approaches for neurological disorders and injuries.

Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.

Genome-wide association studies (GWASs) have identified thousands of variants associated with complex phenotypes, including neuropsychiatric disorders. To better understand their pathogenesis, it is necessary to identify the functional roles of these variants, which are largely located in non-coding DNA regions. Here, we employ a human mesencephalic neuronal cell differentiation model, LUHMES, with sensitive and high-resolution methods to discover enhancers (NET-CAGE), perform DNA conformation analysis (Capture Hi-C) to link enhancers to their target genes, and finally validate selected interactions. We expand the number of known enhancers active in differentiating human LUHMES neurons to 47,350, and find overlap with GWAS variants for Parkinson's disease and schizophrenia. Our findings reveal a fine-tuned regulation of human neuronal differentiation, even between adjacent developmental stages; provide a valuable resource for further studies on neuronal development, regulation, and disorders; and emphasize the importance of exploring the vast regulatory potential of non-coding DNA and enhancers.

Soybean-based foods enhance cognitive functions by influencing hippocampal mechanisms. These salutary effects have so far been attributed to isoflavones present in soybeans. Considering cellular senescence contributes to cognitive decline and that no specific soy-derived peptides are known for their potential to mitigate senescence, we examined the efficacy of a thirteen amino acid soy-derived peptide, Soymetide, on a doxorubicin-induced senescence mice model. Soymetide pretreatment lowered the senescence markers p53, p21 and p16, pro-inflammatory cytokines, and Senescence β-Galactosidase staining while enhancing the mature neuronal marker NeuN in the hippocampus. This anti-senescent effect was comparable with that of a well-known senolytic combination (dasatinib and quercetin). Research indicates that Wnt signaling influences cellular senescence, and our findings here demonstrate that doxorubicin decreased hippocampal Wnt3a, p-LRP6, Frizzled, Dishevelled, Axin1, and β-catenin levels and increased GSK-3β, while Soymetide mitigated these effects. Additionally, upon inhibition of the Wnt/β-catenin pathway, Soymetide's ability to reduce senescence markers and restore NeuN expression was reduced. We validated the anti-senescence impact on hippocampal neurons by co-immunostaining Wnt/β-catenin and senescence indicators alongside NeuN in mice and assessed it in primary hippocampal neurons. Further examining the neuronal survival and functions revealed that Soymetide blocked the doxorubicin-induced loss in Nissl-stained surviving neurons and learning-memory performances, measured by Y-Maze and Passive Avoidance tests, which Wnt/β-catenin inhibitors could counteract. In conclusion, our study identifies a novel Wnt/β-catenin-linked mechanism of doxorubicin-induced senescence in the hippocampal neurons and demonstrates Soymetide's effectiveness in reversing this process. Hence, this suggests Soymetide's potential therapeutic application in addressing cognitive decline associated with cellular aging.

Research shows that chronic pain may induce depression-like behaviors through impairing adult hippocampal neurogenesis (AHN) in the ventral dentate gyrus (DG), whereas restoration of AHN may effectively alleviate depression. The C-X-C motif chemokine receptor 2 (CXCR2) is a chemokine receptor involved in various neural activities of the hippocampus including AHN. In this study we investigated the role of CXCR2 of neural stem cells (NSCs) in the ventral DG in regulating both AHN and depression-like behaviors of mice with chronic neuropathic pain. Chronic neuropathic pain was induced in mice by the spared nerve injury (SNI) surgery; mechanical allodynia and depression-like behaviors were monitored, then mouse DG was collected for analysis. We observed that chronic neuropathic pain significantly decreased the number of immature neurons in the ventral DG by inhibiting the neuronal differentiation of NSCs; specific overexpression of CXCR2 in NSCs by injecting the adeno-associated virus (AAV) into the DG restored adult neurogenesis accompanied by alleviated depression-like behaviors in SNI mice. In contrast, the knockdown of CXCR2 in hippocampal NSCs of naive mice was sufficient to inhibit adult neurogenesis, inducing depression-like behaviors. Moreover, we found that the Wnt3a/β-catenin pathway was downregulated in the ventral DG of SNI mice, which was restored after CXCR2 overexpression or infusing a CXCR2 agonist CXCL1 into the ventral DG. We conclude that CXCR2 expressed in hippocampal NSCs is crucial for regulating adult neurogenesis and chronic pain-induced depression-like behavior, thus representing a new target for the treatment of chronic pain comorbid depression.

Resveratrol (RV) is a natural compound found in grapes, wine, berries, and peanuts and has potential health benefits-namely, neurogenesis improvement. Neurogenesis, which is the process through which new neurons or nerve cells are generated in the brain, occurs in the subventricular zone and hippocampus and is influenced by various factors. RV has been shown to increase neural stem cell proliferation and survival, improving cognitive function in hippocampus-dependent tasks. Thus, to provide a convergent and unbiased conclusion of the available evidence on the correlation between the RV and neurogenesis, a systematic review needs to be undertaken meticulously and with appropriate attention.

This study aimed to systematically review any potential connection between the RV and neurogenesis in animal models.

Based on the particular selection criteria, 8 original animal studies that investigated the relationship between RV and neurogenesis were included. Studies written in English and published in peer-reviewed journals with no restrictions on the starting date of publication on August 17, 2023, were searched in the Google Scholar and PubMed databases. Furthermore, data were extracted and analyzed independently by 2 researchers and then reviewed by a third researcher, and discrepancies were resolved by consensus. This project followed PRISMA reporting standards.

In the studies analyzed in this review, there is a definite correlation between RV and neurogenesis, meaning that RV intake, irrespective of the mechanisms thereof, can boost neurogenesis in both the subventricular zone and hippocampus.

This finding, albeit with some limitations, provides a plausible indication of RV's beneficial function in neurogenesis. Indeed, RV intake may result in neurogenesis benefits-namely, cognitive function, mood regulation, stress resilience, and neuroprotection, potentially preventing cognitive decline.

Cordycepin, the main active component of Cordyceps militaris, exhibits various pharmacological activities, including anti-tumor and antioxidant effects. However, its antidepressant effect and the underlying mechanisms remain unclear.

This study aimed to explore the antidepressant effect of cordycepin and elucidate the potential molecular mechanisms.

Chronic unpredictable mild stress (CUMS) rat model was established to assess antidepressant effect of cordycepin. Gas chromatography-mass spectrometry (GC-MS) metabolomics with integrated network pharmacology were used to find differential metabolites in serum, brain, and cerebrospinal fluid of rats and identify potential target by cordycepin. Western blot and Real-time PCR were applied to validate the signaling pathway.

Cordycepin alleviated CUMS-induced depression-like behaviors by weight gain, sucrose preference increment, immobility time reduction, total travelling distance extension and serum corticosterone levels reduction. Metabolomics showed that cordycepin reversed CUMS-induced metabolic disturbances through alanine and TCA cycle metabolism pathways. Network pharmacology identified GSK3β as a potential target. Cordycepin increased protein levels of p-GSK3β, β-catenin and nuclear β-catenin, and enhanced transcription of downstream genes PKM, LDHA, Cyclin D1 and C-myc in brains of CUMS-induced rats.

This study indicated that cordycepin exerted antidepressant effect by modulating GSK3β/β-catenin pathway, suggesting its potential as a candidate agent for depression.

CTNNB1, which encodes β-catenin, plays an essential role in the Wnt signaling pathway and regulates cellular homeostasis. Mutations in this gene can lead to neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). This study aimed to identify CTNNB1 mutations in two patients presenting with global developmental delay and compare their distinct phenotypes. Next-generation sequencing (NGS) was performed to detect mutations in CTNNB1. Longitudinal clinical observations were conducted to analyze the clinical features of the patients. The first patient was a 7-year-old boy who exhibited symptoms of microcephaly, spasticity, severe amblyopia with retinal detachment, and developmental delay. NGS identified a novel c.1170dupT, p. Ala391CysfsTer4 frameshift variant in CTNNB1. The second patient, a 8-year-old girl, had a dysmorphic face, severe global developmental delay, and ataxic gait. NGS revealed a c.1759C > T, p. Arg587Ter nonsense mutation in CTNNB1. Both patients shared common NEDSDV features; however, distinct phenotypic variations were observed depending on the type of genomic variant. NGS is crucial for the diagnosis of global developmental delay, particularly when brain magnetic resonance imaging (MRI) results appear normal. The identified novel frameshift variant expands the mutational spectrum of CTNNB1.

Stroke is a serious condition often resulting in mortality or long-term disability, causing cognitive, memory, and motor impairments. A reduction in cerebral blood flow below critical levels defines the ischemic core and penumbra: the core undergoes irreversible damage, while the penumbra remains viable but functionally impaired. This functional impairment activates complex cell signaling pathways that determine cell survival or death, making the penumbra a key target for therapeutic interventions to prevent further damage. The Wnt/β-catenin (WβC) signaling pathway has emerged as a potential neuroprotective mechanism, promoting neurogenesis, angiogenesis, neuronal connectivity, and maintaining blood-brain barrier integrity after stroke. Activation of the WβC pathway also mitigates oxidative stress, inflammation, and apoptosis in ischemic regions, enhancing its neuroprotective effects. However, the overexpression of GSK3β and DKK1, or the presence of their agonists, can counteract these benefits. This review explores the therapeutic potential of WβC signaling, highlighting the effects of pharmacological modulation through antagonists, agonists, synthetic chemicals, natural products, stem cells, and macromolecules in preclinical models of ischemic stroke. While preclinical evidence supports the benefits of WβC activation, its role in human stroke requires further investigation. Additionally, the review discusses the potential adverse effects of prolonged WβC activation and suggests strategies to mitigate them. Overall, WβC signaling holds promise as a therapeutic target, offering insights into stroke pathophysiology and informing the development of novel treatment strategies.

In the dentate gyrus of the adult hippocampus, neurogenesis from neural stem cells (NSCs) is regulated by Wnt signals from the local microenvironment. The Wnt/β-catenin pathway is active in NSCs, where it regulates proliferation and fate commitment, and subsequently its activity is strongly attenuated. The mechanisms controlling Wnt activity are poorly understood. In stem cells from adult peripheral tissues, secreted R-spondin proteins (RSPO1-4) interact with LGR4-6 receptors and control Wnt signaling strength. Here, we found that RSPO1-3 and LGR4-6 are expressed in the adult dentate gyrus and in cultured NSCs isolated from the adult mouse hippocampus. LGR4-5 expression decreased in cultured NSCs upon differentiation, concomitantly with the reported decrease in Wnt activity. Treatment with RSPO1-3 increased NSC proliferation and the expression of Cyclin D1 but did not induce the expression of Axin2 or RNF43, 2 well-described Wnt target genes. However, RSPOs enhanced the effect of Wnt3a on Axin2 and RNF43 expression as well as on Wnt/β-catenin reporter activity, indicating that they can potentiate Wnt activity in NSCs. Moreover, RSPO1-3 was found to be expressed by cultured dentate gyrus astrocytes, a crucial component of the neurogenic niche. In co-culture experiments, the astrocyte-induced proliferation of NSCs was prevented by RSPO2 knockdown in astrocytes and LGR5 knockdown in hippocampal NSCs. Additionally, RSPO2 knockdown in the adult mouse dentate gyrus reduced proliferation of neural stem and progenitor cells in vivo. Altogether, our results indicate that RSPO/LGR signaling is present in the dentate gyrus and plays a crucial role in regulating neural precursor cell proliferation.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder that increases the prevalence of cognitive impairment in the geriatric population. Aerobic exercise is an excellent non-pharmacological therapeutic strategy to prevent Alzheimer's disease, the most common form of dementia. The exact molecular mechanism of aerobic exercise (Exe) as an intervention to counter cognitive decline is far from clear. Metformin is a first-line agent against T2DM with neuroprotective properties. The present study assessed the role of treadmill exercise in combination with a low dose of metformin (Met; 70 mg/kg) in cognitive impairment and its associated molecular mechanism in T2DM rats. The experimental model of T2DM-associated cognitive decline was created by administration of a high-fat diet (HFD) with a low dose of streptozotocin (STZ; 35 mg/kg). Neurobehavioral assessments were performed to evaluate spatial recognition and fear-conditioned memory across the groups: control, HFD + STZ, HFD + STZ + Exe, and HFD + STZ + Exe + Met. In addition, we performed immunohistochemistry and western blotting on the rat hippocampal tissue from the above groups for protein expression studies. T2DM rats showed a significant cognitive decline compared to the control group, which improved in the long-term exercise and metformin co-administered animals. The level of neuroinflammation was significantly elevated in the hippocampal tissue of T2DM rats compared to the control and lowered after exercise and metformin treatment. T2DM reduced mature neurons and neurogenesis while increasing astrogliosis and microgliosis, ameliorated by exercise and metformin treatment. Moreover, T2DM impaired hippocampal neurogenesis by reducing the canonical Wnt/β-catenin pathway, which got upregulated in exercise and metformin-co-administered rats. Long-term aerobic exercise with metformin treatment ameliorated neuroinflammation and promoted adult hippocampal neurogenesis via upregulating the canonical Wnt/β-catenin pathway in T2DM rats.

The Wnt/β-catenin signaling pathway plays a pivotal role in the development, maintenance, and repair of the central nervous system (CNS). This chapter explores the diverse functions of Wnt/β-catenin signaling, from its critical involvement in embryonic CNS development to its reparative and plasticity-inducing roles in response to CNS injury. We discuss how Wnt/β-catenin signaling influences various CNS cell types-astrocytes, microglia, neurons, and oligodendrocytes-each contributing to repair and plasticity after injury. The chapter also addresses the pathway's involvement in CNS disorders such as Alzheimer's and Parkinson's diseases, psychiatric disorders, and traumatic brain injury (TBI), highlighting potential Wnt-based therapeutic approaches. Lastly, zebrafish are presented as a promising model organism for studying CNS regeneration and neurodegenerative diseases, offering insights into future research and therapeutic development.

Given their neural crest origin, gingival mesenchymal stem cells (GMSCs) possess high neurogenic potential, which makes them suitable for cell replacement therapy against neurodegenerative diseases. This study investigated whether GMSCs can be transdifferentiated into neurons in vitro using a protocol involving small molecules VCRFY (VPA, CHIR99021, Repsox, Forskolin, and Y-27632). The regulatory mechanisms of key signaling pathways were also investigated.

Neuronal induction of GMSCs was conducted using a small molecules-based protocol over 7 days, which included the evaluation of cell morphology, proliferation, expressions of neurogenic markers, and intracellular calcium oscillation. The activation of canonical the Wnt signaling pathway was assessed by examining the protein content and subcellular localization of β-catenin.

Small molecules-treated GMSCs displayed neuronal morphology and increased expression of neurogenic markers, including class III beta-tubulin (TUJ1), neuron-specific enolase (NSE), microtube-associated protein 2 (MAP2), and neurofilament medium (NFM), verified through RT-qPCR, western blotting, and immunocytochemistry. Based on the results of Fluo-4 AM calcium flux assay, small molecules-treated GMSCs exhibited enhanced electrophysiological activity. GMSC proliferation halted after 2 days of treatment. Among the small molecules, CHIR99021 exhibited the highest neuronal induction efficiency. Furthermore, activation of the Wnt/β-catenin signaling pathway augmented neuronal differentiation.

Small molecule-based cellular reprogramming can efficiently generate neurons from GMSCs, with Wnt/β-catenin signaling to play a critical role in neuronal induction.

Numerous natural antioxidants have been developed into agents for neurodegenerative diseases (NDs) treatment. Rosmarinic acid (RA), an excellent antioxidant, exhibits neuroprotective activity, but its anti-NDs efficacy remains puzzling. Here, Caenorhabditis elegans models were employed to systematically reveal RA-mediated mechanisms in delaying NDs from diverse facets, including oxidative stress, the homeostasis of neural and protein, and mitochondrial disorders. Firstly, RA significantly inhibited reactive oxygen species accumulation, reduced peroxide malonaldehyde production, and strengthened the antioxidant defense system via increasing superoxide dismutase activity. Besides, RA reduced neuronal loss and ameliorated polyglutamine and ɑ-synuclein-mediated dyskinesia in NDs models. Further, in combination with the data and molecular docking results, RA may bind specifically to Huntington protein and ɑ-synuclein to prevent toxic protein aggregation and thus enhance proteostasis. Finally, RA ameliorated mitochondrial dysfunction including increasing adenosine triphosphate and mitochondrial membrane potential levels and rescuing mitochondrial membrane proteins' expressions and mitochondrial structural abnormalities via regulating mitochondrial dynamics genes and improving the mitochondrial kinetic homeostasis. Thus, this study systematically revealed the RA-mediated neuroprotective mechanism and promoted RA as a promising nutritional intervention strategy to prevent NDs.

Deterioration in the neurocognitive function of cancer patients referred to as "Chemobrain" is a devastating obstacle associated with cyclophosphamide (CYP). CYP is an alkylating agent, clinically utilized as an efficient anticancer and immunosuppressant. Coenzyme Q10 (CoQ10) is a worthwhile micronutrient with diverse biological activities embracing antioxidant, anti-apoptotic, and neuroprotective effects. The current experiment was designed for investigating the neuroprotective capability of CoQ10 versus CYP-elicited chemobrain in rats besides elucidating the causal molecular mechanisms. Male Sprague Dawley rats received CoQ10 (10 mg/kg, orally, once daily, for 10 days) and/or a single dose of CYP (200 mg/kg i.p. on day 7). CoQ10 counteracted CYP-induced cognitive and motor dysfunction as demonstrated by the findings of neurobehavioral tests (passive avoidance, Y maze, locomotion, and rotarod tests). Histopathological analysis further affirmed the neuroprotective abilities of CoQ10. CoQ10 effectually diminished CYP-provoked oxidative injury by restoring the antioxidant activity of catalase (CAT) enzyme while reducing malondialdehyde (MDA) levels. Besides, CoQ10 efficiently repressed CYP-induced neuronal apoptosis by downregulating the expression of Bax and caspase-3 while upregulating the Bcl-2 expression. Moreover, CoQ10 hampered CYP-provoked upregulation in acetylcholinesterase (AChE) activity. Furthermore, CoQ10 considerably augmented hippocampal neurogenesis by elevating the expressions of brain-derived neurotrophic factor (BDNF) and Ki-67. These promising neuroprotective effects can be credited to upregulating Wnt/β-catenin pathway as evidenced by the elevated expressions of Wnt-3a, β-catenin, and Phoshpo-glycogen synthase kinase-3 β (p-GSK-3β). Collectively, these findings proved the neuroprotective capabilities of CoQ10 against CYP-induced chemobrain through combating oxidative injury, repressing intrinsic apoptosis, boosting neurogenesis, and eventually upregulating the Wnt/β-catenin pathway.

Neural Stem Progenitor Cells (NSPCs) maintenance and neuronal cell differentiation are the two key aspects of sustained neurogenesis in the adult mammalian brain. Transcription factors (TFs) are known to regulate these biological processes under the influence of various neurotrophic factors. Understanding the role of key TF genes in regulating adult neurogenesis is essential for determining the functional complexity and neuronal diversity seen in the adult mammalian brain. Although several molecular mechanisms leading to adult neurogenesis have been reported, details on its transcriptional regulation are still limited. Our initial results showed that Ciliary Neurotrophic Factor (CNTF) induced neuronal differentiation in SVZ-derived NSPC cultures. To investigate further the role of CNTF in inducing the expression of TF genes related to adult neurogenesis and the potential pathways involved, whole transcriptome RNA-sequencing (RNA-seq) analysis was done in CNTF-treated Sub-ventricular Zone derived neurosphere cultures from the mouse brain. The study revealed 483 differentially expressed genes (DEGs), among which 33 DEGs were identified as coding for transcription factors (TFs). Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis revealed MAPK, PI3K-Akt, and FoxO as the significantly enriched signaling pathways. Gene co-expression network analysis identified five upregulated TF genes related to adult neurogenesis (Runx1, Hmga2, Fos, ID2, and Prrx1) in a single cluster, interacting with each other, and was also validated by quantitative PCR. Our data suggest several potential TFs that may act as critical regulators in the intrinsic transcriptional networks driving the adult neurogenesis process. Further investigation into these molecular regulators may yield a homogeneous population of neuronal progenitors for translational stem cell studies in the future.

Histone deacetylase (HDAC) inhibitors promote differentiation through post-translational modifications of histones. BML-281, an HDAC6 inhibitor, has been known to prevent tumors, acute dextran sodium sulfate-associated colitis, and lung injury. However, the neurogenic differentiation effect of BML-281 is poorly understood. In this study, we investigated the effect of BML-281 on neuroblastoma SH-SY5Y cell differentiation into mature neurons by immunocytochemistry (ICC), reverse transcriptase PCR (RT-PCR), quantitative PCR (qPCR), and western blotting analysis. We found that the cells treated with BML-281 showed neurite outgrowth and morphological changes into mature neurons under a microscope. It was confirmed that the gene expression of neuronal markers (NEFL, MAP2, Tuj1, NEFH, and NEFM) was increased with certain concentrations of BML-281. Similarly, the protein expression of neuronal markers (NeuN, Synaptophysin, Tuj1, and NFH) was upregulated with BML-281 compared to untreated cells. Following treatment with BML-281, the expression of Wnt5α increased, and downstream pathways were activated. Interestingly, both Wnt/Ca2+ and Wnt/PCP pathways activated and regulated PKC, Cdc42, RhoA, Rac1/2/3, and p-JNK. Therefore, BML-281 induces the differentiation of SH-SY5Y cells into mature neurons by activating the non-canonical Wnt signaling pathway. From these results, we concluded that BML-281 might be a novel drug to differentiation into neuronal cells through the regulation of Wnt signaling pathway to reduce the neuronal cell death.

Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI.

Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.

GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.

The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.

Obstructive sleep apnoea (OSA) is a sleep-disordered breathing characterized by intermittent hypoxia (IH) that may cause cognitive dysfunction. However, the impact of IH on molecular processes involved in cognitive function remains unclear.

C57BL / 6 J mice were exposed to either normoxia (control) or IH for 6 weeks. DNA hydroxymethylation was quantified by hydroxymethylated DNA immunoprecipitation (hMeDIP) sequencing. ten-eleven translocation 1 (Tet1) was knocked down by lentivirus. Specifically, cognitive function was assessed by behavioral experiments, pathological features were assessed by HE staining, the hippocampal DNA hydroxymethylation was examined by DNA dot blot and immunohistochemical staining, while the Wnt signaling pathway and its downstream effects were studied using qRT-PCR, immunofluorescence staining, and Luminex liquid suspension chip analysis.

IH mice showed pathological changes and cognitive dysfunction in the hippocampus. Compared with the control group, IH mice exhibited global DNA hydroxylmethylation in the hippocampus, and the expression of three hydroxylmethylases increased significantly. The Wnt signaling pathway was activated, and the mRNA and 5hmC levels of Wnt3a, Ccnd2, and Prickle2 were significantly up-regulated. Further caused downstream neurogenesis abnormalities and neuroinflammatory activation, manifested as increased expression of IBA1 (a marker of microglia), GFAP (a marker of astrocytes), and DCX (a marker of immature neurons), as well as a range of inflammatory cytokines (e.g. TNFa, IL3, IL9, and IL17A). After Tet1 knocked down, the above indicators return to normal.

Activation of Wnt signaling pathway by hippocampal Tet1 is associated with cognitive dysfunction induced by IH.

Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer's (AD) and Parkinson's (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient's age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood-brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host-so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to "silver consumers" demands.

Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations.

Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs.

ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq.

Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer's disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

Neural stem/progenitor cells derived from olfactory neuroepithelium (hereafter olfactory neural stem/progenitor cells, ONSPCs) are emerging as a potential tool in the exploration of psychiatric disorders. The present study intended to assess whether ONSPCs could help discern individuals with schizophrenia (SZ) from non-schizophrenic (NS) subjects by exploring specific cellular and molecular features.

ONSPCs were collected from 19 in-patients diagnosed with SZ and 31 NS individuals and propagated in basal medium. Mitochondrial ATP production, expression of β-catenin and cell proliferation, which are described to be altered in SZ, were examined in freshly isolated or newly thawed ONSPCs after a few culture passages.

SZ-ONSPCs exhibited a lower mitochondrial ATP production and insensitivity to agents capable of positively or negatively affecting β-catenin expression with respect to NS-ONSPCs. As to proliferation, it declined in SZ-ONSPCs as the number of culture passages increased compared to a steady level of growth shown by NS-ONSPCs.

The ease and safety of sample collection as well as the differences observed between NS- and SZ-ONSPCs, may lay the groundwork for a new approach to obtain biological material from a large number of living individuals and gain a better understanding of the mechanisms underlying SZ pathophysiology.

Epilepsy is a neurological disorder characterised by unprovoked, repetitive seizures caused by abnormal neuronal firing. The Wnt/β-Catenin signalling pathway is involved in seizure-induced neurogenesis, aberrant neurogenesis, neuroinflammation, and hyperexcitability associated with epileptic disorder. Wnt/β-Catenin signalling is crucial for early brain development processes including neuronal patterning, synapse formation, and N-methyl-d-aspartate receptor (NMDAR) regulation. Disruption of molecular networks such as Wnt/β-catenin signalling in epilepsy could offer encouraging anti-epileptogenic targets. So, with a better understanding of the canonical Wnt/-Catenin pathway, we highlight in this review the important elements of Wnt/-Catenin signalling specifically in Mesial Temporal Lobe Epilepsy (MTLE) for potential therapeutic targets.

Neurodegenerative diseases, particularly Alzheimer's disease (AD), pose a significant challenge in ageing populations. Our current understanding indicates that the onset of toxic amyloid and tau protein pathologies initiates disease progression. However, existing treatments targeting these hallmark symptoms offer symptomatic relief without halting disease advancement. This review offers an alternative perspective on AD, centring on impaired adult hippocampal neurogenesis (AHN) as a potential early aetiological factor. By delving into the intricate molecular events during the initial stages of AD (Braak Stages I-III), a novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered HS sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.

It was reported that the Wnt/β-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/β-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aβ25-35 peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/β-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aβ25-35. However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/β-catenin pathway.

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer's disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.

Over the last decades, thyroid hormones (THs) signaling has been established as a key signaling cue for the proper maintenance of brain functions in adult mammals, including humans. One of the most fascinating roles of THs in the mature mammalian brain is their ability to regulate adult neurogliogenic processes. In this respect, THs control the generation of new neuronal and glial progenitors from neural stem cells (NSCs) as well as their final differentiation and maturation programs. In this review, we summarize current knowledge on the cellular organization of adult rodent neurogliogenic niches encompassing well-established niches in the subventricular zone (SVZ) lining the lateral ventricles, the hippocampal subgranular zone (SGZ), and the hypothalamus, but also less characterized niches in the striatum and the cerebral cortex. We then discuss critical questions regarding how THs availability is regulated in the respective niches in rodents and larger mammals as well as how modulating THs availability in those niches interferes with lineage decision and progression at the molecular, cellular, and functional levels. Based on those alterations, we explore the novel therapeutic avenues aiming at harnessing THs regulatory influences on neurogliogenic output to stimulate repair processes by influencing the generation of either new neurons (i.e. Alzheimer's, Parkinson's diseases), oligodendrocytes (multiple sclerosis) or both (stroke). Finally, we point out future challenges, which will shape research in this exciting field in the upcoming years.

Neurogenesis, the process of generating functionally integrated neurons from neural stem and progenitor cells, is involved in brain development during embryonic stages but continues throughout life. Adult neurogenesis plays essential roles in many brain functions such as cognition, brain plasticity, and repair. Abnormalities in neurogenesis have been described in many neuropsychiatric and neurological disorders, including epilepsy. While sharing a common property of suppressing seizures, accumulating evidence has shown that some antiseizure medications (ASM) exhibit neuroprotective potential in the non-epileptic models including Parkinson's disease, Alzheimer's disease, cerebral ischemia, or traumatic brain injury. ASM are a heterogeneous group of medications with different mechanisms of actions. Therefore, it remains to be revealed whether neurogenesis is a class effect or related to them all. In this comprehensive literature study, we reviewed the literature data on the influence of ASM on the neurogenesis process during brain development and also in the adult brain under physiological or pathological conditions. Meanwhile, we discussed the underlying mechanisms associated with the neurogenic effects of ASM by linking the reported in vivo and in vitro studies. PubMed, Web of Science, and Google Scholar databases were searched until the end of February 2023. A total of 83 studies were used finally. ASM can modulate neurogenesis through the increase or decrease of proliferation, survival, and differentiation of the quiescent NSC pool. The present article indicated that the neurogenic potential of ASM depends on the administered dose, treatment period, temporal administration of the drug, and normal or disease context.

Primary cilia emanate from most human cell types, including neurons. Cilia are important for communicating with the cell's immediate environment: signal reception and transduction to/from the ciliated cell. Deregulation of ciliary signaling can lead to ciliopathies and certain neurodevelopmental disorders. In the developing brain cilia play well-documented roles for the expansion of the neural progenitor cell pool, while information about the roles of cilia during post-mitotic neuron differentiation and maturation is scarce.

We employed ciliated Lund Human Mesencephalic (LUHMES) cells in time course experiments to assess the impact of ciliary signaling on neuron differentiation. By comparing ciliated and non-ciliated neuronal precursor cells and neurons in wild type and in RFX2 -/- mutant neurons with altered cilia, we discovered an early-differentiation "ciliary time window" during which transient cilia promote axon outgrowth, branching and arborization. Experiments in neurons with IFT88 and IFT172 ciliary gene knockdowns, leading to shorter cilia, confirm these results. Cilia promote neuron differentiation by tipping WNT signaling toward the non-canonical pathway, in turn activating WNT pathway output genes implicated in cyto-architectural changes.

We provide a mechanistic entry point into when and how ciliary signaling coordinates, promotes and translates into anatomical changes. We hypothesize that ciliary alterations causing neuron differentiation defects may result in "mild" impairments of brain development, possibly underpinning certain aspects of neurodevelopmental disorders.

The sex chromosome, especially specific in one sex, generally determines sexual size dimorphism (SSD), a phenomenon with dimorphic sexual difference in the body size. For Cynoglossus semilaevis, a flatfish in China, although the importance of chromosome W and its specific gene zbed1 in female-biased SSD have been suggested, its family members and regulation information are still unknown. At present, three zbed1 copies gene were identified on chromosome W, with no gametologs. Phylogenetic analysis for the ZBED family revealed an existence of ZBED9 in the fish. Nine members were uncovered from C. semilaevis, clustering into three kinds, ZBED1, ZBED4 and ZBEDX, which is less than the eleven kinds of ZBED members in mammals. The predominant expression of zbed1 in the female brain and pituitary tissues was further verified by qPCR. Transcription factor c/ebpα could significantly enhance the transcriptional activity of zbed1 promoter, which is opposite to its effect on the male determinant factor-dmrt1. When zbed1 was interfered with, piwil1, esr2 and wnt7b were up-regulated, while cell-cycle-related genes, including cdk4 and ccng1, were down-regulated. Thus, zbed1 is involved in cell proliferation by regulating esr2, piwil1, cell cycle and the Wnt pathway. Further research on their interactions would be helpful to understand fish SSD.

Neural plasticity can be defined as the ability of neural circuits to be shaped by external and internal factors. It provides the brain with a capacity for functional and morphological remodelling, with many lines of evidence indicating that these changes are vital for learning and memory formation. The basis of this brain plasticity resides in activity- and experience-driven modifications of synaptic strength, including synaptic formation, elimination or weakening, as well as of modulation of neuronal population, which drive the structural reorganization of neural networks. Recent evidence indicates that brain-resident glial cells actively participate in these processes, suggesting that mechanisms underlying plasticity in the brain are multifaceted. Establishing the 'tripartite' synapse, the role of astrocytes in modulating synaptic transmission in response to neuronal activity was recognized first. Further redefinition of the synapse as 'quad-partite' followed to acknowledge the contribution of microglia which were revealed to affect numerous brain functions via dynamic interactions with synapses, acting as 'synaptic sensors' that respond to neuronal activity and neurotransmitter release, as well as crosstalk with astrocytes. Early studies identified microglial ability to dynamically survey their local brain environment and established their integral role in the active interfacing of environmental stimuli (both internal and external), with brain plasticity and remodelling. Following the introduction to neurogenesis, this chapter details the role that microglia play in regulating neurogenesis in adulthood, specifically as it relates to learning and memory, as well as factors involved in modulation of microglia. Further, a microglial perspective is introduced for the context of environmental enrichment impact on neurogenesis, learning and memory across states of stress, ageing, disease and injury.