Synaptic Formation Research Articles

The immune synapses reveal aberrant functions of CD8 T cells during chronic HIV infection

Chronic HIV infection causes persistent low-grade inflammation that induces premature aging of the immune system including senescence of memory and effector CD8 T cells. To uncover the reasons of gradually diminished potency of CD8 T cells from people living with HIV, here we expose the T cells to planar lipid bilayers containing ligands for T-cell receptor and a T-cell integrins and analyze the cellular morphology, dynamics of synaptic interface formation and patterns of the cellular degranulation. We find a large fraction of phenotypically naive T cells from chronically infected people are capable to form mature synapse with focused degranulation, a signature of a differentiated T cells. Further, differentiation of aberrant naive T cells may lead to the development of anomalous effector T cells undermining their capacity to control HIV and other pathogens that could be contained otherwise.

Rapid Eye Movement Sleep during Early Life: A Comprehensive Narrative Review.

The ontogenetic sleep hypothesis suggested that rapid eye movement (REM) sleep is ontogenetically primitive. Namely, REM sleep plays an imperative role in the maturation of the central nervous system. In coincidence with a rapidly developing brain during the early period of life, a remarkably large amount of REM sleep has been identified in numerous behavioral and polysomnographic studies across species. The abundant REM sleep appears to serve to optimize a cerebral state suitable for homeostasis and inherent neuronal activities favorable to brain maturation, ranging from neuronal differentiation, migration, and myelination to synaptic formation and elimination. Progressively more studies in Mammalia have provided the underlying mechanisms involved in some REM sleep-related disorders (e.g., narcolepsy, autism, attention deficit hyperactivity disorder (ADHD)). We summarize the remarkable alterations of polysomnographic, behavioral, and physiological characteristics in humans and Mammalia. Through a comprehensive review, we offer a hybrid of animal and human findings, demonstrating that early-life REM sleep disturbances constitute a common feature of many neurodevelopmental disorders. Our review may assist and promote investigations of the underlying mechanisms, functions, and neurodevelopmental diseases involved in REM sleep during early life.

The effects of Memantine and MK801 on NMDA receptor switching 2B and 2A subunits in hippocampal cell culture.

Background: Schizophrenia (SCZ) is a severe and chronic neurodevelopmental disorder which onset begins in adolescence or early adulthood. Notwithstanding, the brain dysfunction occurs before the disease and involves the NMDA receptor switch from GluN2B to GluN2A at early neonatal period. We have recently postulated memantine (MEM) as an effective experimental treatment, which may have its root on the modulation of NMDA receptor subunit turnover during the postnatal period by preventing glutamatergic hypofunction in the maternal deprivation model of SCZ. Methods: To explore this possibility, here we have evaluated the turn-over of pre and postsynaptic glutamatergic synaptic components by using primary mouse hippocampal neurons during the synaptic formation period. Results: MK801 stimulation prevented the GluN2B to GluN2A molecular switch at 11 days in vitro (DIV). Importantly, vesicular glutamate transporter 2 (VGLUT2) was also reduced at this time point. MEM treatment reverted these effects by normalizing GluN2B, GluN2A and overexpressing VGLUT2 expression. Conclusion: Our data supports a mechanism by which behavioral abnormalities previously observed in animals after maternal deprivation may be prevented by MEM treatment by regulation of the glutamatergic synaptic molecular composition.

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases.

Astrocytes are the most abundant cells in the brain. They have many important functions in the central nervous system (CNS), including the maintenance of glutamate and ion homeostasis, the elimination of oxidative stress, energy storage in glycogen, tissue repair, regulating synaptic activity by releasing neurotransmitters, and participating in synaptic formation. Astrocytes have special highly ramified structure. Their branches contact with synapses of neurons inwardly, with fine structure and wrapping synapses; their feet contact with blood vessels of brain parenchyma outward, almost wrapping the whole brain. The adjacent astrocytes rarely overlap and communicate with each other through gap junction channels. The ideal location of astrocytes enables them to sense the weak changes of their surroundings and provide the structural basis for the energy supply of neurons. Neurons and astrocytes are closely coupled units of energy metabolism in the brain. Neurons consume a lot of ATPs in the process of neurotransmission. Astrocytes provide metabolic substrates for neurons, maintain high activity of neuron, and facilitate information transmission of neurons. This article reviews the characteristics of glucose metabolism, lipid metabolism, and amino acid metabolism of astrocytes. The metabolic interactions between astrocytes and neurons, astrocytes and microglia were also detailed discussed. Finally, we classified analyzed the role of metabolic disorder of astrocytes in the occurrence and development of neurodegenerative diseases.

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs’ Wnt/β-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.

In the developing cerebral cortex: axonogenesis, synapse formation, and synaptic plasticity are regulated by SATB2 target genes.

Special AT-rich sequence-binding protein 2 is essential for the development of cerebral cortex and key molecular node for the establishment of proper neural circuitry and function. Mutations inthe SATB2 gene lead to SATB2-associated syndrome, which is characterized by abnormal development of skeleton and central nervous systems. We generated Satb2 knockout mouse model through CRISPR-Cas9 technology and performed RNA-seq and ChIP-seq of embryonic cerebral cortex. We conducted RT-qPCR, western blot, immunofluorescence staining, luciferase reporter assay and behavioral analysis for experimental verification. We identified 1363 downstream effector genes of Satb2 and correlation analysis of Satb2-targeted genes and neurological disease genes showed that Satb2 contribute to cognitive and mental disorders from theearly developmental stage. We found thatSatb2 directly regulate the expression of Ntng1, Cdh13, Kitl, genes important for axon guidance, synaptic formation, neuron migration, and Satb2 directly activates theexpression of Mef2c. We also showed thatSatb2 heterozygous knockout mice showed impaired spatial learning and memory. Taken together, our study supportsroles of Satb2 in the regulation of axonogenesis and synaptic formation at theearly developmental stage and provides new insights into the complicated regulatory mechanism of Satb2 and new evidence to elucidate the pathogen of SATB2-associated syndrome. 1363 downstream effector genes of Satb2 were classified into 5 clusters with different temporal expression patterns. We identified Plxnd1, Ntng1, Efnb2, Ephb1, Plxna2, Epha3, Plxna4, Unc5c, and Flrt2 as axon guidance molecules to regulate axonogenesis. 168 targeted genes of Satb2 were found to regulate synaptic formation in the early development of the cerebral cortex. Transcription factor Mef2c is positively regulated by Satb2, and 28 Mef2c-targeted genes can be directly regulated by Satb2. In the Morris water maze test, Satb2+/- mice showed impaired spatial learning and memory, further strengthening that Satb2 can regulate synaptic functions.

Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer's disease pathology in mice.

All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.

Regulation of the Human IL-10RB Gene Expression by Sp8 and Sp9.

Interleukin-10 (IL-10) is a classic anti-inflammatory cytokine that exerts its effects via the receptor complexes IL-10RA and IL-10RB. Loss of IL-10RB results in many diseases. Moreover, IL-10RB is closely associated with neuronal survival and synaptic formation. However, the regulation of IL-10RB gene expression remains elusive. To investigate whether the expression of IL-10RB gene is increased in brain of Alzheimer's disease (AD) and its transcriptional regulation. We examined the gene expression of AD patient brain from public database and detected the protein expression of AD model mouse brain by western blot. We constructed a variety of reporter gene plasmids with different lengths or mutation sites, tested the promoter activity and defined the functional region of the promoter with the luciferase reporter assay. The protein-DNA binding between transcription factors and the promoter was analyzed using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). We found that the IL-10RB is elevated in the brain of AD patient and AD model mice. The minimal promoter of the IL-10RB gene is located in the -90 to +51 bp region (relative to the transcriptional start site) and is sufficient for high-level expression of the IL-10RB gene. Transcription factors Sp8 and Sp9 bind to the IL-10RB promoter in vitro. The overexpression or knockdown of Sp8 and Sp9 affected the IL-10RB promoter activity and its gene expression. Our study functionally characterized the promoter of the IL-10RB gene and demonstrated that Sp8 and Sp9 regulated its expression.

Local mRNA translation and cytoskeletal reorganization: Mechanisms that tune neuronal responses.

Neurons are highly polarized cells with significantly long axonal and dendritic extensions that can reach distances up to hundreds of centimeters away from the cell bodies in higher vertebrates. Their successful formation, maintenance, and proper function highly depend on the coordination of intricate molecular networks that allow axons and dendrites to quickly process information, and respond to a continuous and diverse cascade of environmental stimuli, often without enough time for communication with the soma. Two seemingly unrelated processes, essential for these rapid responses, and thus neuronal homeostasis and plasticity, are local mRNA translation and cytoskeletal reorganization. The axonal cytoskeleton is characterized by high stability and great plasticity; two contradictory attributes that emerge from the powerful cytoskeletal rearrangement dynamics. Cytoskeletal reorganization is crucial during nervous system development and in adulthood, ensuring the establishment of proper neuronal shape and polarity, as well as regulating intracellular transport and synaptic functions. Local mRNA translation is another mechanism with a well-established role in the developing and adult nervous system. It is pivotal for axonal guidance and arborization, synaptic formation, and function and seems to be a key player in processes activated after neuronal damage. Perturbations in the regulatory pathways of local translation and cytoskeletal reorganization contribute to various pathologies with diverse clinical manifestations, ranging from intellectual disabilities (ID) to autism spectrum disorders (ASD) and schizophrenia (SCZ). Despite the fact that both processes are essential for the orchestration of pathways critical for proper axonal and dendritic function, the interplay between them remains elusive. Here we review our current knowledge on the molecular mechanisms and specific interaction networks that regulate and potentially coordinate these interconnected processes.

NMDA receptor-targeted enrichment of CaMKIIα improves fear memory

SummaryThe establishment of effective molecular interventions to improve memory and alleviate memory deficits in disease remains a long-standing challenge despite growing molecular understanding of synaptic plasticity and memory formation. Capitalizing on the fact that long-term potentiation (LTP) requires N-methyl-D-aspartate receptors (NMDARs) and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα), we develop an intrabody that targets NMDARs and show that intrabody-mediated postsynaptic enrichment of CaMKIIα in the hippocampus improves contextual fear memory. This molecular approach suggests a potential demand for effective targeting of postsynaptic molecules to enhance memory and provides insights into studying memory improvement in health and disease.

Presynaptic supervision of cortical spine dynamics in motor learning.

In mammalian neocortex, learning triggers the formation and turnover of new postsynaptic spines on pyramidal cell dendrites. However, the biological principles of spine reorganization during learning remain elusive because the identity of their presynaptic neuronal partners is unknown. Here, we show that two presynaptic neural circuits supervise distinct programs of spine dynamics to execute learning. We imaged spine dynamics in motor cortex during learning and performed post hoc identification of their afferent presynaptic neurons. New spines that appeared during learning formed small transient contacts with corticocortical neurons that were eliminated on skill acquisition. In contrast, persistent spines with axons from thalamic neurons were formed and enlarged. These results suggest that pyramidal cell dendrites in motor cortex use a neural circuit division of labor during skill learning, with dynamic teaching contacts from top-down intracortical axons followed by synaptic memory formation driven by thalamic axons. Dual spine supervision may govern diverse skill learning in the neocortex.

Multiple knockout mouse and embryonic stem cell models reveal the role of miR-124a in neuronal maturation

MicroRNA-124a (miR-124a) is one of the most abundantly expressed microRNAs in the central nervous system and is encoded in mammals by the three genomic loci miR-124a-1/2/3; however, its in vivo roles in neuronal development and function remain ambiguous. In the present study, we investigated the effect of miR-124a loss on neuronal differentiation in mice and in embryonic stem (ES) cells. Since miR-124a-3 exhibits only background expression levels in the brain and we were unable to obtain miR-124a-1/2/3 triple knockout (TKO) mice by mating, we generated and analyzed miR-124a-1/2 double knockout (DKO) mice. We found that these DKO mice exhibit perinatal lethality. RNA-seq analysis demonstrated that the expression levels of proneural and neuronal marker genes were almost unchanged between the control and miR-124a-1/2 DKO brains; however, genes related to neuronal synaptic formation and function were enriched among downregulated genes in the miR-124a-1/2 DKO brain. In addition, we found the transcription regulator Tardbp/TDP-43, loss of which leads to defects in neuronal maturation and function, was inactivated in the miR-124a-1/2 DKO brain. Furthermore, Tardbp knockdown suppressed neurite extension in cultured neuronal cells. We also generated miR-124a-1/2/3 TKO ES cells using CRISPR-Cas9 as an alternative to TKO mice. Phase-contrast microscopic, immunocytochemical, and gene expression analyses showed that miR-124a-1/2/3 TKO ES cell lines were able to differentiate into neurons. Collectively, these results suggest that miR-124a plays a role in neuronal maturation rather than neurogenesis in vivo and advance our understanding of the functional roles of microRNAs in central nervous system development.

TARC and Septin 7 can be better monitoring biomarkers than CX3CL1, sICAM5, and IRF5 in children with seizure-free epilepsy with monotherapy and drug-resistant epilepsy

Aim: To evaluate i) the relationship between epilepsy and inflammation by analyzing the levels of thymus activation-regulated chemokine (TARC), and interferon regulatory factor 5 (IRF5) in healthy controls, patients with epilepsy on monotherapy and polytherapy, ii) the levels of sICAM5, chemokine (c-x3-c motif) ligand 1 (CX3CL1), and septin 7 (SEPT7) which are important in both inflammation and synaptic formation. Methods: Patients who were seizure-free with monotherapy (epilepsy group-1), patients with drug-resistant epilepsy (epilepsy group-2), and healthy controls were included. Demographical data, disease durations, and medications were noted. Measurements were made by commercial ELISA kits. Results: The numbers of epilepsy group-1, epilepsy group-2, and healthy controls were 23, 20, and 21, respectively. TARC levels were significantly lower in healthy controls than in both epilepsy groups. Higher TARC levels than 0.58 pg/ml indicated epilepsy with a sensitivity of 81.8% and specificity of 84.0%. SEPT7 levels were significantly higher in epilepsy group-1 than in those epilepsy group-2. A negative correlation was found between SEPT7 levels and disease duration as is the case for the correlation between SEPT7 and average seizure duration. A positive correlation was found between IRF5 and CX3CL1 levels, SEPT7 and IRF5 levels, and IRF5 and sICAM5 levels. Conclusions: We suggest that TARC is a promising biomarker, even in a heterogeneous epilepsy group not only for drug-resistance epilepsy but also for seizure-free epilepsy with monotherapy. Additionally, drug resistance, longer disease, and longer seizure durations are related to lower levels of SEPT7, which has an essential role in immunological functions and dendritic morphology.

Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation.

Fragile X mental retardation protein (FMRP) is an mRNA-binding protein that regulates local protein translation. FMRP loss or dysfunction leads to aberrant neuronal and synaptic activities in fragile X syndrome (FXS), which is characterized by intellectual disability, sensory abnormalities, and social communication problems. Studies of FMRP function and FXS pathogenesis have primarily been conducted with Fmr1 (the gene encoding FMRP) knockout in transgenic animals. Here we report an in vivo method for determining the cell-autonomous function of FMRP during the period of circuit assembly and synaptic formation using chicken embryos. This method employs stage-, site-, and direction-specific electroporation of a drug-inducible vector system containing Fmr1 small hairpin RNA (shRNA) and an EGFP reporter. With this method, we achieved selective FMRP knockdown in the auditory ganglion (AG) and in one of its brainstem targets, the nucleus magnocellularis (NM), thus providing a component-specific manipulation within the AG-NM circuit. Additionally, the mosaic pattern of the transfection allows within-animal controls and neighboring neuron/fiber comparisons for enhanced reliability and sensitivity in data analyzing. The inducible vector system provides temporal control of gene editing onset to minimize accumulating developmental effects. The combination of these strategies provides an innovative tool to dissect the cell-autonomous function of FMRP in synaptic and circuit development.

Bisphenol-A impairs synaptic formation and function by RGS4-mediated regulation of BDNF signaling in the cerebral cortex.

ABSTRACTBisphenol-A (BPA) is a representative endocrine disruptor, widely used in a variety of products including plastics, medical equipment and receipts. Hence, most people are exposed to BPA via the skin, digestive system or inhalation in everyday life. Furthermore, BPA crosses the blood–brain barrier and is linked to multiple neurological dysfunctions found in neurodegenerative and neuropsychological disorders. However, the mechanisms underlying BPA-associated neurological dysfunctions remain poorly understood. Here, we report that BPA exposure alters synapse morphology and function in the cerebral cortex. Cortical pyramidal neurons treated with BPA showed reduced size and number of dendrites and spines. The density of excitatory synapses was also decreased by BPA treatment. More importantly, we found that BPA disrupted normal synaptic transmission and cognitive behavior. RGS4 and its downstream BDNF/NTRK2 pathway appeared to mediate the effect of BPA on synaptic and neurological function. Our findings provide molecular mechanistic insights into anatomical and physiological neurotoxic consequences related to a potent endocrine modifier.

Lost in Translation: Neurotrophins Biology and Function in the Neurovascular Unit.

The neurovascular unit (NVU) refers to the functional building unit of the brain and the retina, where neurons, glia, and microvasculature orchestrate to meet the demand of the retina's and brain's function. Neurotrophins (NTs) are structural families of secreted proteins and are known for exerting neurotrophic effects on neuronal differentiation, survival, neurite outgrowth, synaptic formation, and plasticity. NTs include several molecules, such as nerve growth factor, brain-derived neurotrophic factor, NT-3, NT-4, and their precursors. Furthermore, NTs are involved in signaling pathways such as inflammation, apoptosis, and angiogenesis in a nonneuronal cell type. Interestingly, NTs and the precursors can bind and activate the p75 neurotrophin receptor (p75NTR) at low and high affinity. Mature NTs bind their cognate tropomyosin/tyrosine-regulated kinase receptors, crucial for maintenance and neuronal development in the brain and retina axis. Activation of p75NTR results in neuronal apoptosis and cell death, while tropomysin receptor kinase upregulation contributes to differentiation and cell growth. Recent findings indicate that modulation of NTs and their receptors contribute to neurovascular dysfunction in the NVU. Several chronic metabolic and acute ischemic diseases affect the NVU, including diabetic and ischemic retinopathy for the retina, as well as stroke, acute encephalitis, and traumatic brain injury for the brain. This work aims to review the current evidence through published literature studying the impact of NTs and their receptors, including the p75NTR receptor, on the injured and healthy brain-retina axis.

Deletion of Wnt10a Is Implicated in Hippocampal Neurodegeneration in Mice.

The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely unclear. Here, we examined the morphological and functional alterations in the hippocampus of Wnt10a-knockout (Wnt10a-/-) mice. Neurobehavioral tests revealed that Wnt10a-/- mice exhibited spatial memory impairment and anxiety-like behavior. Immunostaining and Western blot findings showed that the protein expressions of β-catenin, brain-derived neurotrophic factor, and doublecortin were significantly decreased and that the number of activated microglia increased, accompanied by amyloid-β accumulation, synaptic dysfunction, and microglia-associated neuroinflammation in the hippocampi of Wnt10a-/- mice. Our findings revealed that the deletion of Wnt10a decreased neurogenesis, impaired synaptic function, and induced hippocampal neuroinflammation, eventually leading to hippocampal neurodegeneration and memory deficit, possibly through the β-catenin signaling pathway, providing a novel insight into preventive approaches for hippocampus-dependent cognitive impairment.

The Transcription Factor, α1ACT, Acts Through a MicroRNA Network to Regulate Neurogenesis and Cell Death During Neonatal Cerebellar Development

MicroRNAs, a class of small RNA regulators, function throughout neurodevelopment, from neural stem cell neurogenesis to neuronal maturation, synaptic formation, and plasticity. α1ACT, a transcription factor (TF), plays a critical role in neonatal cerebellar development by regulating an ensemble of genes. Of these, ChIP-seq analysis matched near 50% genes directly regulated by α1ACT. Yet, more than half the regulated transcripts lacked direct interaction with α1ACT. To investigate whether α1ACT acts through a microRNA network, we studied α1ACT-associated simultaneous miRNA:mRNA transcriptome profiles, using miRNA-seq paired with RNA-seq. Thirty-one differentially expressed miRNAs (DEMs) associated with α1ACT-regulated differentially expressed genes (DEGs) were profiled in α1ACT-overexpressing PC12 cells and were further validated in neonatal transgenic mouse cerebellum overexpressing α1ACT in a context-dependent manner. Here, we also demonstrated that α1ACT facilitates neurogenesis and development of dendritic synapses and is partially a result of the downregulation of the miR-99 cluster, miR-143, miR-23, miR-146, miR-363, and miR-484. On the other hand, the miR-181, miR-125, and miR-708 clusters were upregulated by α1ACT, which inhibit MAPK signaling and cell death pathways by targeting Ask1, Odc1, Atf4, and Nuf2 for decreased expression. MiR-181a-5p was verified as the most abundant DEM in neonatal cerebellum, which was further induced by α1ACT. Overall, under α1ACT modulation, up-/downregulated miRNA clusters with their paired target genes may form a regulatory network controlling the balance between the neuronal proliferation, differentiation, and cell death in the cerebellum to promote neonatal development. Our findings concerning the α1ACT-related miRNA/mRNA expression profiles in neonatal cerebellum may inform future investigations for cerebellar development.

The Role of Mesenchymal Stem Cells in Regulating Astrocytes-Related Synapse Dysfunction in Early Alzheimer's Disease.

Alzheimer’s disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Regulation and function of elF2B in neurological and metabolic disorders.

Eukaryotic initiation factor 2B, eIF2B is a guanine nucleotide exchange, factor with a central role in coordinating the initiation of translation. During stress and disease, the activity of eIF2B is inhibited via the phosphorylation of its substrate eIF2 (p-eIF2α). A number of different kinases respond to various stresses leading to the phosphorylation of the alpha subunit of eIF2, and collectively this regulation is known as the integrated stress response, ISR. This targeting of eIF2B allows the cell to regulate protein synthesis and reprogramme gene expression to restore homeostasis. Advances within structural biology have furthered our understanding of how eIF2B interacts with eIF2 in both the productive GEF active form and the non-productive eIF2α phosphorylated form. Here, current knowledge of the role of eIF2B in the ISR is discussed within the context of normal and disease states focusing particularly on diseases such as vanishing white matter disease (VWMD) and permanent neonatal diabetes mellitus (PNDM), which are directly linked to mutations in eIF2B. The role of eIF2B in synaptic plasticity and memory formation is also discussed. In addition, the cellular localisation of eIF2B is reviewed and considered along with the role of additional in vivo eIF2B binding factors and protein modifications that may play a role in modulating eIF2B activity during health and disease.