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1.
World J Surg Oncol ; 20(1): 146, 2022 May 10.
Article En | MEDLINE | ID: mdl-35538578

BACKGROUND: Glioblastoma is one of the most aggressive tumors. The etiology and the factors determining its onset are not yet entirely known. This study investigates the origins of GBM, and for this purpose, it focuses primarily on developmental gliogenic processes. It also focuses on the impact of the related neurogenic developmental processes in glioblastoma oncogenesis. It also addresses why glial cells are at more risk of tumor development compared to neurons. METHODS: Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving glioblastoma, gliogenesis, neurogenesis, stemness, neural stem cells, gliogenic signaling and pathways, neurogenic signaling and pathways, and astrocytogenic genes. RESULTS: The origin of GBM is dependent on dysregulation in multiple genes and pathways that accumulatively converge the cells towards oncogenesis. There are multiple layers of steps in glioblastoma oncogenesis including the failure of cell fate-specific genes to keep the cells differentiated in their specific cell types such as p300, BMP, HOPX, and NRSF/REST. There are genes and signaling pathways that are involved in differentiation and also contribute to GBM such as FGFR3, JAK-STAT, and hey1. The genes that contribute to differentiation processes but also contribute to stemness in GBM include notch, Sox9, Sox4, c-myc gene overrides p300, and then GFAP, leading to upregulation of nestin, SHH, NF-κB, and others. GBM mutations pathologically impact the cell circuitry such as the interaction between Sox2 and JAK-STAT pathway, resulting in GBM development and progression. CONCLUSION: Glioblastoma originates when the gene expression of key gliogenic genes and signaling pathways become dysregulated. This study identifies key gliogenic genes having the ability to control oncogenesis in glioblastoma cells, including p300, BMP, PAX6, HOPX, NRSF/REST, LIF, and TGF beta. It also identifies key neurogenic genes having the ability to control oncogenesis including PAX6, neurogenins including Ngn1, NeuroD1, NeuroD4, Numb, NKX6-1 Ebf, Myt1, and ASCL1. This study also postulates how aging contributes to the onset of glioblastoma by dysregulating the gene expression of NF-κB, REST/NRSF, ERK, AKT, EGFR, and others.


Brain Neoplasms , Glioblastoma , Brain Neoplasms/pathology , Carcinogenesis/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Humans , Janus Kinases/genetics , Janus Kinases/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplastic Stem Cells/metabolism , Neurogenesis , SOXC Transcription Factors/genetics , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , Signal Transduction
2.
Science ; 376(6595): eabn6204, 2022 05 20.
Article En | MEDLINE | ID: mdl-35587969

In the forebrain, ventrally derived oligodendrocyte precursor cells (vOPCs) travel tangentially toward the cortex together with cortical interneurons. Here, we tested in the mouse whether these populations interact during embryogenesis while migrating. By coupling histological analysis of genetic models with live imaging, we show that although they are both attracted by the chemokine Cxcl12, vOPCs and cortical interneurons occupy mutually exclusive forebrain territories enriched in this chemokine. Moreover, first-wave vOPC depletion selectively disrupts the migration and distribution of cortical interneurons. At the cellular level, we found that by promoting unidirectional contact repulsion, first-wave vOPCs steered the migration of cortical interneurons away from the blood vessels to which they were both attracted, thereby allowing interneurons to reach their proper cortical territories.


Oligodendrocyte Precursor Cells , Animals , Cell Movement/genetics , Cerebral Cortex , Interneurons/physiology , Mice , Neurogenesis
3.
Mol Brain ; 15(1): 38, 2022 May 02.
Article En | MEDLINE | ID: mdl-35501905

Adult neurogenesis, the proliferation and integration of newly generated neurons, has been observed in the adult mammalian hippocampus of many species. Numerous studies have also found adult neurogenesis in the human hippocampus, but several recent high-profile studies have suggested that this process is considerably reduced in humans, occurring in children but not in adults. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. These differences may represent biological species differences or could alternatively be explained by methodological differences in tissue handling and fixation. Here, we examine whether differences in the post-mortem interval between death and tissue fixation might impact subsequent detection of adult neurogenesis due to increased tissue degradation. Because there are fewer new neurons present in older subjects to begin with we hypothesized that, subject age might interact significantly with post-mortem interval in the detection of adult neurogenesis. We analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis.


Neurogenesis , Neurons , Aged , Animals , Hippocampus/physiology , Humans , Mammals , Neurons/physiology , Rats
4.
Development ; 149(8)2022 Apr 15.
Article En | MEDLINE | ID: mdl-35502778

In fishes and salamanders, but not mammals, neural stem cells switch back to neurogenesis after injury. The signalling environment of neural stem cells is strongly altered by the presence of damaged cells and an influx of immune, as well as other, cells. Here, we summarise our recently expanded knowledge of developmental, physiological and immune signals that act on neural stem cells in the zebrafish central nervous system to directly, or indirectly, influence their neurogenic state. These signals act on several intracellular pathways, which leads to changes in chromatin accessibility and gene expression, ultimately resulting in regenerative neurogenesis. Translational approaches in non-regenerating mammals indicate that central nervous system stem cells can be reprogrammed for neurogenesis. Understanding signalling mechanisms in naturally regenerating species show the path to experimentally promoting neurogenesis in mammals.


Neural Stem Cells , Zebrafish , Animals , Central Nervous System/physiology , Mammals , Nerve Regeneration/physiology , Neural Stem Cells/physiology , Neurogenesis/physiology , Zebrafish/physiology
5.
Zool Res ; 43(3): 481-496, 2022 May 18.
Article En | MEDLINE | ID: mdl-35503338

Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD.


Alzheimer Disease , Alzheimer Disease/veterinary , Animals , Brain , Hippocampus , Humans , Mammals , Neurogenesis/physiology , Neurons
6.
Science ; 376(6590): eabn7270, 2022 04 15.
Article En | MEDLINE | ID: mdl-35504021

Rakic and colleagues challenge the use of extensively validated adult hippocampal neurogenesis (AHN) markers and postulate an alternative interpretation of some of the data included in our study. In Terreros-Roncal et al., reconstruction of the main stages encompassed by human AHN revealed enhanced vulnerability of this phenomenon to neurodegenerative diseases. Here, we clarify points and ambiguities raised by these authors.


Neurodegenerative Diseases , Adult , Biomarkers , Hippocampus/physiology , Humans , Neurogenesis/physiology
7.
Adv Exp Med Biol ; 1360: 117-148, 2022.
Article En | MEDLINE | ID: mdl-35505167

The growth arrest and DNA damage-inducible (Gadd) 45 proteins have been associated with numerous cellular mechanisms including cell cycle control, DNA damage sensation and repair, genotoxic stress, neoplasia, and molecular epigenetics. The genes were originally identified in in vitro screens of irradiation- and interleukin-induced transcription and have since been implicated in a host of normal and aberrant central nervous system processes. These include early and postnatal development, injury, cancer, memory, aging, and neurodegenerative and psychiatric disease states. The proteins act through a variety of molecular signaling cascades including the MAPK cascade, cell cycle control mechanisms, histone regulation, and epigenetic DNA demethylation. In this review, we provide a comprehensive discussion of the literature implicating each of the three members of the Gadd45 family in these processes.


Cell Cycle Proteins , Nuclear Proteins , Cell Cycle Checkpoints , Cell Cycle Proteins/metabolism , Epigenesis, Genetic , Neurogenesis/genetics , Nuclear Proteins/metabolism
8.
Stem Cells ; 40(1): 59-73, 2022 03 03.
Article En | MEDLINE | ID: mdl-35511865

Increased neurogenesis elicits antidepressive-like effects. The antidiabetic drug metformin (Met) reportedly promotes hippocampal neurogenesis, which ameliorates spatial memory deficits and depression-like behaviors. However, the precise molecular mechanisms underpinning Met-induced neuronal differentiation of neural stem cells (NSCs) remain unclear. We showed that Met enhanced neuronal differentiation of NSCs via Gadd45g but not Gadd45a and Gadd45b. We further found that Gadd45g increased demethylation of neurogenic differentiation 1 promoter by regulating the activity of passive and active DNA demethylation enzymes through an adenylate-activated protein kinase -independent mechanism in Met-treated NSCs. Importantly, genetic deficiency of Gadd45g decreased hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors in the adult mice, whereas forced expression of Gadd45g alleviated the depressive-like behaviors. Our findings provide a model that Gadd45g-mediated DNA demethylation contributes to Met-induced neuronal genesis and its antidepressant-like effects and propose the concept that targeting Gadd45g regulation of neurogenesis might serve as a novel antidepressant strategy.


Metformin , Neural Stem Cells , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Antigens, Differentiation/genetics , Antigens, Differentiation/metabolism , DNA Demethylation , Hippocampus/metabolism , Metformin/metabolism , Metformin/pharmacology , Mice , Neural Stem Cells/metabolism , Neurogenesis
9.
Biomed Res Int ; 2022: 4065118, 2022.
Article En | MEDLINE | ID: mdl-35528162

Background: Neuroprotective effects of stem cells have been shown in some neurologic diseases. In this study, the effect of oral mucosal mesenchymal stem cells (OMSCs) on traumatic brain injury (TBI) was evaluated in long term. Materials and Methods: TBI was induced by Marmarou's method. The number of 2 × 106 OMSCs was intravenously injected 1 and 24 h after the injury. Brain edema and pathological outcome were assessed at 24 h and 21 days after the injury. Besides, long-term neurological, motor, and cognitive outcomes were evaluated at days 3, 7, 14, and 21 after the injury. Results: OMSCs administration could significantly inhibit microglia proliferation, and reduce brain edema and neuronal damage, at 24 h and 21 days after the injury. Neurological function improvement was observed in the times evaluated in OMSCs group. Cognitive and motor function dysfunction and anxiety-like behavior were prevented especially at 14 and 21 days after the injury in the treatment group. Conclusion: According to the results of this study, OMSCs administration after TBI reduced brain edema and neuronal damage, improved neurologic outcome, and prevented memory and motor impairments and anxiety-like behavior in long term.


Brain Edema , Brain Injuries, Traumatic , Mesenchymal Stem Cells , Neuroprotective Agents , Animals , Disease Models, Animal , Neurogenesis , Neuroprotective Agents/pharmacology
10.
J Vis Exp ; (182)2022 Apr 20.
Article En | MEDLINE | ID: mdl-35532257

Astrocytes possess an astounding degree of morphological complexity that enables them to interact with nearly every type of cell and structure within the brain. Through these interactions, astrocytes actively regulate many critical brain functions, including synapse formation, neurotransmission, and ion homeostasis. In the rodent brain, astrocytes grow in size and complexity during the first three postnatal weeks and establish distinct, non-overlapping territories to tile the brain. This protocol provides an established method for analyzing astrocyte territory volume and astrocyte tiling using free-floating tissue sections from the mouse brain. First, this protocol describes the steps for tissue collection, cryosectioning, and immunostaining of free-floating tissue sections. Second, this protocol describes image acquisition and analysis of astrocyte territory volume and territory overlap volume, using commercially available image analysis software. Lastly, this manuscript discusses the advantages, important considerations, common pitfalls, and limitations of these methods. This protocol requires brain tissue with sparse or mosaic fluorescent labeling of astrocytes, and is designed to be used with common lab equipment, confocal microscopy, and commercially available image analysis software.


Astrocytes , Neurogenesis , Animals , Brain/metabolism , Image Processing, Computer-Assisted , Mice , Microscopy, Confocal/methods
11.
Nat Neurosci ; 25(5): 630-645, 2022 May.
Article En | MEDLINE | ID: mdl-35524139

Adult hippocampal neurogenesis plays a critical role in memory and emotion processing, and this process is dynamically regulated by neural circuit activity. However, it remains unknown whether manipulation of neural circuit activity can achieve sufficient neurogenic effects to modulate behavior. Here we report that chronic patterned optogenetic stimulation of supramammillary nucleus (SuM) neurons in the mouse hypothalamus robustly promotes neurogenesis at multiple stages, leading to increased production of neural stem cells and behaviorally relevant adult-born neurons (ABNs) with enhanced maturity. Functionally, selective manipulation of the activity of these SuM-promoted ABNs modulates memory retrieval and anxiety-like behaviors. Furthermore, we show that SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Moreover, SuM is required for ABN activity-dependent behavioral modulation under a novel environment. Our study identifies a key hypothalamic circuit that couples novelty signals to the production and maturation of ABNs, and highlights the activity-dependent contribution of circuit-modified ABNs in behavioral regulation.


Hippocampus , Neurogenesis , Animals , Anxiety , Hippocampus/physiology , Hypothalamus , Memory/physiology , Mice , Mice, Inbred C57BL , Neurogenesis/physiology
12.
Cells ; 11(7)2022 04 06.
Article En | MEDLINE | ID: mdl-35406805

Neuronal growth regulator 1 (NEGR1) is a brain-enriched membrane protein that is involved in neural cell communication and synapse formation. Accumulating evidence indicates that NEGR1 is a generic risk factor for various psychiatric diseases including autism and depression. Endoglycosidase digestion of single NEGR1 mutants revealed that the wild type NEGR1 has six putative N-glycosylation sites partly organized in a Golgi-dependent manner. To understand the role of each putative N-glycan residue, we generated a series of multi-site mutants (2MT-6MT) with additive mutations. Cell surface staining and biotinylation revealed that NEGR1 mutants 1MT to 4MT were localized on the cell surface at different levels, whereas 5MT and 6MT were retained in the endoplasmic reticulum to form highly stable multimer complexes. This indicated 5MT and 6MT are less likely to fold correctly. Furthermore, the removal of two N-terminal sites N75 and N155 was sufficient to completely abrogate membrane targeting. An in vivo binding assay using the soluble NEGR1 protein demonstrated that glycans N286, N294 and N307 on the C-terminal immunoglobulin-like domain play important roles in homophilic interactions. Taken together, these results suggest that the N-glycan moieties of NEGR1 are closely involved in the folding, trafficking, and homodimer formation of NEGR1 protein in a site-specific manner.


Cell Adhesion Molecules , Endoplasmic Reticulum , Cell Adhesion Molecules/metabolism , Endoplasmic Reticulum/metabolism , Glycosylation , Neurogenesis , Polysaccharides/metabolism
13.
Cell Death Dis ; 13(4): 292, 2022 Apr 01.
Article En | MEDLINE | ID: mdl-35365601

microRNA-592 (miR-592) has been linked to neurogenesis, but the influence of miR-592 knockout in vivo remains unknown. Here, we report that miR-592 knockout represses IPC-to-mature neuron transition, impairs motor coordination and reduces social interaction. Combining the RNA-seq and tandem mass tagging-based quantitative proteomics analysis (TMT protein quantification) and luciferase reporter assays, we identified MeCP2 as the direct targetgene of miR-592 in the mouse cortex. In Tg(MECP2) mice, lipofection of miR-592 efficiently reduced MECP2 expression in the brains of Tg(MECP2) mice at E14.5. Furthermore, treatment with miR-592 partially ameliorated the autism-like phenotypes observed in adult Tg(MECP2) mice. The findings demonstrate that miR-592 might play a novel role in treating the neurodevelopmental-associated disorder.


MicroRNAs , Social Interaction , Animals , Brain/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Neurogenesis/genetics , Neurons/metabolism
14.
Nat Neurosci ; 25(4): 458-473, 2022 Apr.
Article En | MEDLINE | ID: mdl-35379995

Hydrocephalus, characterized by cerebral ventricular dilatation, is routinely attributed to primary defects in cerebrospinal fluid (CSF) homeostasis. This fosters CSF shunting as the leading reason for brain surgery in children despite considerable disease heterogeneity. In this study, by integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), we found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH.


Hydrocephalus , Animals , Biomechanical Phenomena , Brain/metabolism , Cerebrospinal Fluid/metabolism , Humans , Hydrocephalus/cerebrospinal fluid , Hydrocephalus/genetics , Mice , Neurogenesis/genetics , Tripartite Motif Proteins/genetics , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/genetics , Whole Exome Sequencing
15.
Pharmacol Res ; 179: 106235, 2022 May.
Article En | MEDLINE | ID: mdl-35472635

Adult hippocampal neurogenesis (AHN) is heavily implicated in the pathogenesis of various neuropsychiatric disorders. The mangiferin (MGF), a bioactive compound of the mango, reportedly produces biological effects on a variety of neuropsychiatric disorders. However, the function and underlying mechanisms of MGF in regulating hippocampal neurogenesis remain unknown. Here we discovered that the transcriptome and methylome of MGF-induced neural stem cells (NSCs) are distinct from the control. RNA-seq analysis revealed that the diferentially expressed genes (DEGs) were signifcantly enriched in the PPARs. Furthermore, we found that MGF enhanced neuronal differentiation and proliferation of neural stem cells (NSCs) via PPARß but not PPARα and PPARγ. The combination of WGBS and RNA-seq analysis showed that the expression of some neurogenesis genes was negatively correlated with the DNA methylation level generally. We further found that PPARß increased demethylation of Mash1 promoter by modulating the expressions of active and passive DNA demethylation enzymes in MGF-treated NSCs. Importantly, genetic deficiency of PPARß decreased hippocampal neurogenesis in the adult mice, whereas the defective neurogenesis was notably rescued by Mash1 overexpression. Our findings uncover a model that PPARß-mediated DNA demethylation of Mash1 contributes to MGF-induced neuronal genesis, and advance the concept that targeting PPARß-TET1/DNMT3a-Mash1 axis regulation of neurogenesis might serve as a novel neurotherapeutic strategy.


Neural Stem Cells , PPAR delta , PPAR-beta , Animals , DNA Demethylation , Mice , Neurogenesis , PPAR-beta/genetics , PPAR-beta/metabolism , Xanthones
16.
Life Sci Alliance ; 5(8)2022 Aug.
Article En | MEDLINE | ID: mdl-35470239

Protein O-GlcNAcylation is a dynamic, nutrient-sensitive mono-glycosylation deposited on numerous nucleo-cytoplasmic and mitochondrial proteins, including transcription factors, epigenetic regulators, and histones. However, the role of protein O-GlcNAcylation on epigenome regulation in response to nutrient perturbations during development is not well understood. Herein we recapitulated early human embryonic neurogenesis in cell culture and found that pharmacological up-regulation of O-GlcNAc levels during human embryonic stem cells' neuronal differentiation leads to up-regulation of key neurogenic transcription factor genes. This transcriptional de-repression is associated with reduced H3K27me3 and increased H3K4me3 levels on the promoters of these genes, perturbing promoter bivalency possibly through increased EZH2-Thr311 phosphorylation. Elevated O-GlcNAc levels also lead to increased Pol II-Ser5 phosphorylation and affect H2BS112O-GlcNAc and H2BK120Ub1 on promoters. Using an in vivo rat model of maternal hyperglycemia, we show similarly elevated O-GlcNAc levels and epigenetic dysregulations in the developing embryo brains because of hyperglycemia, whereas pharmacological inhibition of O-GlcNAc transferase (OGT) restored these molecular changes. Together, our results demonstrate O-GlcNAc mediated sensitivity of chromatin to nutrient status, and indicate how metabolic perturbations could affect gene expression during neurodevelopment.


Acetylglucosamine , Hyperglycemia , Acetylglucosamine/metabolism , Animals , Epigenesis, Genetic , Neurogenesis/genetics , Nutrients , Rats , Transcriptome
17.
Front Neural Circuits ; 16: 866999, 2022.
Article En | MEDLINE | ID: mdl-35463203

Sensory information is transduced into electrical signals in the periphery by specialized sensory organs, which relay this information to the thalamus and subsequently to cortical primary sensory areas. In the cortex, microcircuits constituted by interconnected pyramidal cells and inhibitory interneurons, distributed throughout the cortical column, form the basic processing units of sensory information underlying sensation. In the mouse, these circuits mature shortly after birth. In the first postnatal week cortical activity is characterized by highly synchronized spontaneous activity. While by the second postnatal week, spontaneous activity desynchronizes and sensory influx increases drastically upon eye opening, as well as with the onset of hearing and active whisking. This influx of sensory stimuli is fundamental for the maturation of functional properties and connectivity in neurons allocated to sensory cortices. In the subsequent developmental period, spanning the first five postnatal weeks, sensory circuits are malleable in response to sensory stimulation in the so-called critical periods. During these critical periods, which vary in timing and duration across sensory areas, perturbations in sensory experience can alter cortical connectivity, leading to long-lasting modifications in sensory processing. The recent advent of intersectional genetics, in vivo calcium imaging and single cell transcriptomics has aided the identification of circuit components in emergent networks. Multiple studies in recent years have sought a better understanding of how genetically-defined neuronal subtypes regulate circuit plasticity and maturation during development. In this review, we discuss the current literature focused on postnatal development and critical periods in the primary auditory (A1), visual (V1), and somatosensory (S1) cortices. We compare the developmental trajectory among the three sensory areas with a particular emphasis on interneuron function and the role of inhibitory circuits in cortical development and function.


Interneurons , Neurons , Animals , Interneurons/physiology , Mice , Neurogenesis , Neurons/physiology , Parietal Lobe , Pyramidal Cells
18.
Oxid Med Cell Longev ; 2022: 3716609, 2022.
Article En | MEDLINE | ID: mdl-35464765

Takeda G protein-coupled receptor 5 (TGR5) is the first known G protein-coupled receptor specific for bile acids and is recognized as a new and critical target for type 2 diabetes and metabolic syndrome. It is expressed in many brain regions associated with memory such as the hippocampus and frontal cortex. Here, we hypothesize that activation of TGR5 may ameliorate streptozotocin- (STZ-) induced cognitive impairment. The mouse model of cognitive impairment was established by a single intracerebroventricular (ICV) injection of STZ (3.0 mg/kg), and we found that TGR5 activation by its agonist INT-777 (1.5 or 3.0 µg/mouse, ICV injection) ameliorated spatial memory impairment in the Morris water maze and Y-maze tests. Importantly, INT-777 reversed STZ-induced downregulation of TGR5 and glucose usage deficits. Our results further showed that INT-777 suppressed neuronal apoptosis and improved neurogenesis which were involved in tau phosphorylation and CREB-BDNF signaling. Moreover, INT-777 increased action potential firing of excitatory pyramidal neurons in the hippocampal CA3 and medial prefrontal cortex of ICV-STZ groups. Taken together, these findings reveal that activation of TGR5 has a neuroprotective effect against STZ-induced cognitive impairment by modulating apoptosis, neurogenesis, and neuronal firing in the brain and TGR5 might be a novel and potential target for Alzheimer's disease.


Alzheimer Disease , Cognitive Dysfunction , Diabetes Mellitus, Type 2 , Alzheimer Disease/metabolism , Animals , Apoptosis , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Hippocampus/metabolism , Maze Learning , Mice , Neurogenesis , Receptors, G-Protein-Coupled/metabolism , Streptozocin/toxicity
19.
Cell Death Dis ; 13(4): 325, 2022 Apr 09.
Article En | MEDLINE | ID: mdl-35397630

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/ß-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/ß-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the ß-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/ß-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/ß-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-ß-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.


Alzheimer Disease , Wnt Signaling Pathway , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Disease Models, Animal , Hippocampus/metabolism , Ki-67 Antigen/metabolism , Mice , Neurogenesis/physiology , Neurons/metabolism , Simvastatin/pharmacology , Simvastatin/therapeutic use , beta Catenin/metabolism
20.
Int J Mol Sci ; 23(8)2022 Apr 08.
Article En | MEDLINE | ID: mdl-35456950

In the fascinating landscape of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are peeping out as a new promising and appreciated class of molecules with great potential as diagnostic and prognostic biomarkers. They come from circularization of single-stranded RNA molecules covalently closed and generated through alternative mRNA splicing. Dismissed for many years, similar to aberrant splicing by-products, nowadays, their role has been regained. They are able to regulate the expression of linear mRNA transcripts at different levels acting as miRNA sponges, interacting with ribonucleoproteins or exerting a control on gene expression. On the other hand, being extremely conserved across phyla and stable, cell and tissue specific, mostly abundant than the linear RNAs, it is not surprising that they should have critical biological functions. Curiously, circRNAs are particularly expressed in brain and they build up during aging and age-related diseases. These extraordinary peculiarities make circRNAs potentially suitable as promising molecular biomarkers, especially of aging and neurodegenerative diseases. This review aims to explore new evidence on circRNAs, emphasizing their role in aging and pathogenesis of major neurodegenerative disorders, Alzheimer's disease, frontotemporal dementia, and Parkinson's diseases with a look toward their potential usefulness in biomarker searching.


MicroRNAs , Neurodegenerative Diseases , Biomarkers , Humans , MicroRNAs/genetics , Neurodegenerative Diseases/genetics , Neurogenesis/genetics , RNA, Circular/genetics , RNA, Messenger
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