Cells Of Nervous System Research Articles

SUMOylation of TRIM28 is positively modulated by the BTB/POZ domain of Kaiso.

TRIM28 plays a crucial role in maintaining genomic stability and establishing imprinting, facilitated by the diversity of KRAB zinc finger proteins. The SUMOylation of TRIM28 is essential for its function and is enhanced in the presence of the KRAB domain. Previously, we demonstrated that Kaiso, another factor capable of interacting with TRIM28, can promote its SUMOylation. Here we investigate which structural elements of Kaiso are necessary for the hyper-SUMOylation of TRIM28. We found that the SUMO-interacting motifs (SIMs) of Kaiso are not responsible for TRIM28 SUMOylation. The SUMOylation of individual TRIM28 domains in the presence of Kaiso was not observed, suggesting the importance of TRIM28's structural integrity for this process. The Kaiso BTB/POZ domain, but not its closest homolog ZBTB4, is sufficient for the effective hyper-SUMOylation of TRIM28. Also, using single-cell sequencing data of mouse embryos, we identified cells in which co-expression of Kaiso and TRIM28 occurs, including the immune system, nervous system and various epithelial cells. BTB/POZ domain of Kaiso may function similarly to KRAB domains in its interaction with TRIM28 regulating its SUMOylation.

Functional differentiation of human dental pulp stem cells into neuron-like cells exhibiting electrophysiological activity

Background and aimHuman dental pulp stem cells (hDPSCs) constitute a promising alternative for central nervous system (CNS) cell therapy. Unlike other human stem cells, hDPSCs can be differentiated, without genetic modification, to neural cells that secrete neuroprotective factors. However, a better understanding of their real capacity to give rise to functional neurons and integrate into synaptic networks is still needed. For that, ex vivo differentiation protocols must be refined, especially to avoid the use of fetal animal serum. The aim of our study is to improve existing differentiation protocols of hDPSCs into neuron-like cells.MethodsWe compared the effects of the (1) absence or presence of fetal serum during the initial expansion phase as a step prior to switching cultures to neurodifferentiation media. We (2) improved hDPSC neurodifferentiation by adding retinoic acid (RA) and potassium chloride (KCl) pulses for 21 or 60 days and characterized the results by immunofluorescence, digital morphometric analysis, RT-qPCR and electrophysiology.ResultsWe found that neural markers like Nestin, GFAP, S100β and p75NTR were expressed differently in neurodifferentiated hDPSC cultures depending on the presence or absence of serum during the initial cell expansion phase. In addition, hDPSCs previously grown as spheroids in serum-free medium exhibited in vitro expression of neuronal markers such as doublecortin (DCX), neuronal nuclear antigen (NeuN), Ankyrin-G and MAP2 after neurodifferentiation. Presynaptic vGLUT2, Synapsin-I, and excitatory glutamatergic and inhibitory GABAergic postsynaptic scaffold proteins and receptor subunits were also present in these neurodifferentiated hDPSCs. Treatment with KCl and RA increased the amount of both voltage-gated Na+ and K+ channel subunits in neurodifferentiated hDPSCs at the transcript level. Consistently, these cells displayed voltage-dependent K+ and TTX-sensitive Na+ currents as well as spontaneous electrophysiological activity and repetitive neuronal action potentials with a full baseline potential recovery.ConclusionOur study demonstrates that hDPSCs can be differentiated to neuronal-like cells that display functional excitability and thus evidence the potential of these easily accessible human stem cells for nerve tissue engineering. These results highlight the importance of choosing an appropriate culture protocol to successfully neurodifferentiate hDPSCs.

Phagocytic Function Analyses of GABBR-Related Microglia in Immature Developing Epileptic Brain Based on 10× Single-Nucleus RNA Sequencing Technology

Background: Epilepsy is a neurological disorder defined by the occurrence of epileptic seizures, which can significantly affect children, often leading to learning and cognitive impairments. Microglia, the resident immune cells of the central nervous system, are essential in clearing damaged neurons through phagocytosis. Notably, GABBR-associated microglia have been implicated in regulating phagocytic activity. Since the phagocytic function of microglia is critical in the pathogenesis of epilepsy, this study aims to investigate the role of GABBR-associated microglia in the development of the immature brain following epileptic seizures. Methods: Epilepsy was induced in a mouse model by the intraperitoneal injection of KA. Changes in the expression of the GABBR-related gene, GABBR2, in hippocampal microglia were analyzed using single-nucleus RNA sequencing (snRNA-seq). Cognitive and emotional changes in the mice were assessed through behavioral analyses. The expression of GABBR2 was semi-quantitatively measured using Western blotting, quantitative reverse transcription PCR, and immunofluorescence. Additionally, the spatial relationship between GABBR2 and hippocampal neurons was evaluated using Imaris software. Results: The snRNA-seq analysis revealed that GABBR2 expression was elevated in activated microglia in the hippocampus during chronic epilepsy compared to the early phase of seizures. Behavioral assessments demonstrated heightened anxiety levels and learning and memory impairments in the chronic epilepsy group compared to the control group. GABBR2 expression was upregulated in chronic epilepsy. Three-dimensional reconstruction analyses revealed a significantly increased contact volume between GABBR-associated microglia and neurons in the chronic epilepsy group compared to the control group. Conclusions: GABBR-associated microglia significantly contribute to the progression of immature brain diseases by promoting neuronal phagocytic activity.

Glial-derived TNF/Eiger signaling promotes somatosensory neurite sculpting

The selective elimination of inappropriate projections is essential for sculpting neural circuits during development. The class IV dendritic arborization (C4da) sensory neurons of Drosophila remodel the dendritic branches during metamorphosis. Glial cells in the central nervous system (CNS), are required for programmed axonal pruning of mushroom body (MB) γ neurons during metamorphosis in Drosophila. However, it is entirely unknown whether the glial cells are involved in controlling the neurite pruning of C4da sensory neurons. Here, we show that glial deletion of Eiger (Egr), orthologous to mammalian tumor necrosis factor TNF superfamily ligand, results in dendrite remodeling deficiency of Drosophila C4da sensory neurons. Moreover, the attenuation of neuronal Wengen (Wgn) and Grindelwald (Grnd), the receptors for TNF ligands, is also examined for defects in dendrite remodeling. We further discover that Wgn and Grnd facilitate dendrite elimination through the JNK Signaling. Overall, our findings demonstrate that glial-derived Egr signal links to the neuronal receptor Wgn/Grnd, activating the JNK signaling pathway and promoting developmental neuronal remodeling. Remarkably, our findings reveal a crucial role of peripheral glia in dendritic pruning of C4da neurons.

Microglial modulation of neuronal network function and plasticity.

Microglia are the resident immune cells of the central nervous system (CNS), which have been classically viewed as involved in CNS responses to damage and tissue repair. However, microglia are constantly sensing neuronal network activity and changes in the CNS milieu, establishing complex state-dependent microglia-neuron interactions that impact their functions. By doing so, microglia perform a wide range of physiological roles, including brain homeostasis maintenance, control of neural connectivity, network function modulation, as well as functional and morphological plasticity regulation in health and disease. Here, I review recent evidence of the modulations induced by microglia, a highly heterogeneous cell type, on synaptic and intrinsic neuronal properties, as well as on neuronal network patterns during perinatal development and adulthood. The reviewed evidence clearly indicate that microglia are important, if not essential, for brain function and plasticity in both health and disease.

Mechanisms Underlying the Size-Dependent Neurotoxicity of Polystyrene Nanoplastics in Zebrafish.

Nanoplastics (NPs) are ubiquitous in the environment, posing significant threats to biological systems, including nervous systems, across various trophic levels. Nevertheless, the molecular mechanisms behind the size-dependent neurotoxicity of NPs remain unclear. Here, we investigated the neurotoxicity of 20 and 100 nm polystyrene NPs (PS-NPs) to zebrafish. Utilizing molecular dynamics simulations and complementary methods, we discovered that PS-NPs initiated neurotoxicity by promoting dimerization of the toll-like receptor 4/myeloid differentiation-2 (TLR4/MD-2) complex. This process involves the binding of PS-NPs to the hydrophobic pocket of MD-2, which induced the flipping of Phe-126 toward the dimer interface and the bending of the C-terminal domain of TLR-4, bringing the two domains into close proximity. Thereafter, the astrocytes and microglia were activated, initiating a cascade of events that include neuroinflammation, central nervous system cell apoptosis, inhibition of motor neuron development, and ultimately alteration of the swimming behavior of zebrafish. Further, 20 nm PS-NPs elicited more severe neurotoxicity than 100 nm PS-NPs, attributed to their higher accumulation in the brain as determined through 14C-labeled PS-NPs and more effective interaction with the TLR4/MD-2 complex. Overall, our study uncovers the mechanisms underlying the size-dependent neurotoxicity of NPs, which merit attention during their risk assessment and regulation.

Human neural rosettes secrete bioactive extracellular vesicles enriched in neuronal and glial cellular components

Extracellular vesicles (EVs) play a critical role in the development of neural cells in the central nervous system (CNS). Human neural rosettes (hNRs) are radial cell structures that assemble from induced pluripotent stem cells (hiPSCs) and recapitulate some stages of neural tube morphogenesis. Here we show that hiPSCs and hNRs secrete EVs (hiPSC-EVs and hNR-EVs) with distinctive protein cargoes. Remarkably, hNR-EVs carry neuronal and glial cellular components involved in human CNS development. Importantly, hNR-EVs stimulate stem cells to change their cellular morphology and promote neurite growth in human and murine neurons with a significant dysregulation of SOX2 levels. This transcription factor modulates both neural differentiation and pluripotency. Interestingly, these effects were inhibited by antibodies against an unexpected neuroglial cargo of hNR-EVs: the major proteolipid protein (PLP). These findings show that hNRs secrete bioactive EVs containing neural components and might contribute as trophic factors during human neurodevelopment.

Netrin-1's Protective Effect on A-Burdened BV2 Microglial Cells Enhanced Its Viability of Peptide Drugs for Alzheimers Disease Treatment

The rising prevalence of Alzheimers Disease (AD) has stimulated extensive research into novel therapeutic strategies. Current studies suggest peptide-based drugs are emerging as promising candidates targeting various aspects of AD pathophysiology. Microglia play a crucial role in AD due to their functions as the resident immune cells in the central nervous system, and are a prominent target for the development of peptide drugs. Netrin-1, a brain-derived extracellular factor, demonstrated therapeutic potential in AD by modulating microglial function. Here, we investigated the effects of netrin-1 on amyloid-beta (A)-burden microglia using BV2 microglial cells as a model. Cell counting was performed to assess the cell viability under different concentrations of netrin-1. Immunofluorescence was employed to examine morphological changes associated with microglial activation. To examine the polarization towards M1 or M2 phenotypes, fluorescence detection was performed after amplification. ELISA quantified A concentration to assess the protective effect of netrin-1. Microglial gene expression influenced by A was identified in the Gene Expression Omnibus (GEO) database (GSE227221). Expression levels of netrin-1 receptors were analyzed to identify potential targets. Protein structures from the RCSB database were docked with netrin-1 using PyMOL to identify the amino acids on the binding interface that may stimulate the receptors and mitigate A-induced damage. Specifically, a concentration of 100 ng/mL of netrin-1 optimally maintained cell viability in the presence of A. Netrin-1 could lessen A-induced microglial activation, especially M2 activation phenotype. ELISA data showed that netrin-1 treatment significantly improved the phagocytic abilities of A-burden BV2 cells. Analysis of the GEO database revealed that the expressions of DCC, DSCAM, and UNC5a were significantly elevated following A treatment in microglia. Eight potential polypeptides were identified as the potential targets for netrin-1 binding. In conclusion, netrin-1 mitigated the A-induced damage in microglia through its protective effects. The eight identified peptides of netrin-1 may represent a significant advancement toward developing drugs targeting A-related AD pathology. Netrin-1 based peptide drugs hold novel therapeutic promise for AD

Epilepsy therapy beyond neurons: unveiling astrocytes as cellular targets.

Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation-inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drug-resistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.

Developmental axon diameter growth of central nervous system axons does not depend on ensheathment or myelination by oligodendrocytes.

Myelination facilitates the rapid conduction of action potentials along axons. In the central nervous system (CNS), myelinated axons vary over 100-fold in diameter, with conduction speed scaling linearly with increasing diameter. Axon diameter and myelination are closely interlinked, with axon diameter exerting a strong influence on myelination. Conversely, myelinating Schwann cells in the peripheral nervous system can both positively and negatively affect axon diameter. However, whether axon diameter is regulated by CNS oligodendrocytes is less clear. Here, we investigated CNS axon diameter growth in the absence of myelin using mouse (Mbp shi/shi and Myrf conditional knockout) and zebrafish (olig2 morpholino) models. We find that neither the ensheathment of axons, nor the formation of compact myelin are required for CNS axons to achieve appropriate and diverse diameters. This indicates that developmental CNS axon diameter growth is independent of myelination, and shows that myelinating cells of CNS and PNS differentially influence axonal morphology.

From cell to organ: Exploring the toxicological correlation of organophosphorus compounds in living system.

Malathion is an organophosphate compound widely used as an insecticide in the agriculture sector and is toxic to humans and other mammals. Although several studies have been conducted at different levels in different animal models. But there is no work has been conducted on the toxicological correlation from cellular to behavioral level in surviving species model. Addressing this gap through further research is essential for a comprehensive understanding of malathion's impact on biological systems, facilitating better risk assessment and management strategies. Current research systemically evaluated the effects of malathion on the central nervous system and peripheral immune cells using immunological techniques in the BALB/c mice models. For this, animals were placed inside an inhalation chamber containing malathion (dose of 89.5 mg/ml/m3) for a specific exposure time. The group exposed for 6 minutes has shown a significant change in plasma-neurotransmitter (serotonin, dopamine) levels and decreased expression of Tyrosine hydroxylase in striatum and SNPC region of brain. The depolarized mitochondria and increased level of cleaved caspase-3 level and mature neurons in DG, CA1 and CA3 were also observed in the brain. Peripheral blood analysis illustrated a decrease in total leukocyte count and an increased level of early apoptosis at the same time point. From neurobehavioral results a significant locomotor hyperactivity, restlessness, and risk-taking behavior was observed. Taken together, results from the current study indicate that exposure to malathion at prolonged time durations induces neuronal and immune cell toxicity, and its toxicity may be mediated via changes in neurotransmitter levels and metabolite concentrations.

LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3.

Aging leads to cognitive decline and increased risk of neurodegenerative diseases. While molecular changes in central nervous system (CNS) cells contribute to this decline, the mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) are key regulators of cellular functions. Background/Objectives: The roles of lncRNAs in aging, especially in glial cells, are not well characterized. Methods: We investigated lncRNA expression in non-neuronal cells from aged mice and identified 3222401L13Rik, a previously unstudied lncRNA, as upregulated in astrocytes during aging. Results: Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes for neuronal support and synapse organization, a function conserved in human iPSC-derived astrocytes. A 3222401L13Rik interacts with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and overexpression of Npas3 rescues deficits in astrocytes lacking 3222401L13Rik. Conclusions: These data suggest that 3222401L13Rik upregulation may help delay age-related cognitive decline.

Glial cells improve Parkinson's disease by modulating neuronal function and regulating neuronal ferroptosis.

The main characteristics of Parkinson's disease (PD) are the loss of dopaminergic (DA) neurons and abnormal aggregation of cytosolic proteins. However, the exact pathogenesis of PD remains unclear, with ferroptosis emerging as one of the key factors driven by iron accumulation and lipid peroxidation. Glial cells, including microglia, astrocytes, and oligodendrocytes, serve as supportive cells in the central nervous system (CNS), but their abnormal activation can lead to DA neuron death and ferroptosis. This paper explores the interactions between glial cells and DA neurons, reviews the changes in glial cells during the pathological process of PD, and reports on how glial cells regulate ferroptosis in PD through iron homeostasis and lipid peroxidation. This opens up a new pathway for basic research and therapeutic strategies in Parkinson's disease.

Recent advances in the role of neuroregulation in skin wound healing.

Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.

Impacts of hnRNP A1 Splicing Inhibition on the Brain Remyelination Proteome.

Oligodendrocytes, the myelinating cells in the central nervous system, are implicated in several neurological disorders marked by dysfunctional RNA-binding proteins (RBPs). The present study aimed at investigating the role of hnRNP A1 in the proteome of the corpus callosum, prefrontal cortex, and hippocampus of a murine cuprizone-induced demyelination model. Right after the cuprizone insult, we administered an hnRNP A1 splicing activity inhibitor and analyzed its impact on brain remyelination by nanoESI-LC-MS/MS label-free proteomic analysis to assess the biological processes affected in these brain regions. Significant alterations in essential myelination proteins highlighted the involvement of hnRNP A1 in maintaining myelin integrity. Pathways related to sphingolipid and endocannabinoid signaling were affected, as well as the synaptic vesicle cycle and GABAergic synapses. Although behavioral impairments were not observed, molecular changes suggest potential links to memory, synaptic function, and neurotransmission processes. These findings enhance our understanding of the multifaceted roles of hnRNP A1 in the central nervous system, providing valuable insights for future investigations and therapeutic interventions in neurodegenerative and demyelinating diseases.

Fundamental Neurochemistry Review: Lipids across microglial states.

The capacity of immune cells to alter their function based on their metabolism is the basis of the emerging field of immunometabolism. Microglia are the resident innate immune cells of the central nervous system, and it is a current focus of the field to investigate how alterations in their metabolism impact these cells. Microglia have the ability to utilize lipids, such as fatty acids, as energy sources, but also alterations in lipids can impact microglial form and function. Recent studies highlighting different microglial states and transcriptional signatures have highlighted modifications in lipid processing as defining these states. This review highlights these recent studies and uses these altered pathways to discuss the current understanding of lipid biology in microglia. The studies highlighted here review how lipids may alter microglial phagocytic functioning or alter their pro- and anti-inflammatory balance. These studies provide a foundation by which lipid supplementation or diet alterations could influence microglial states and function. Furthermore, targets modulating microglial lipid metabolism may provide new treatment avenues.

The Role of Microglia in Parkinson's Disease and Possible Therapeutic Targets

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to significant motor and non-motor symptoms. Recent research highlights the critical role of microglia, the resident immune cells of the central nervous system, in the pathogenesis and progression of PD. Microglia contribute to neuroinflammation through the release of pro-inflammatory cytokines and reactive oxygen species, exacerbating neuronal damage. Moreover, α-synuclein aggregates, a hallmark of PD, activate microglia, further promoting inflammation and neurodegeneration. This review explores the dual role of microglia in PD, encompassing both their neuroprotective functions and their contribution to neuroinflammation. We discuss the molecular mechanisms underlying microglial activation and their interactions with astrocytes, another crucial glial cell type. The review also examines potential therapeutic targets aimed at modulating microglial activity to mitigate neuroinflammation and slow the progression of PD. Current therapeutic strategies predominantly focus on symptomatic relief through dopaminergic medications. However, emerging therapies targeting microglial activation, such as anti-inflammatory drugs, immunomodulators, and novel agents like metabotropic glutamate receptor 5 (mGluR5) modulators, offer promising avenues for disease modification. Understanding the complex interplay between microglia and other cellular components in the PD brain is essential for developing effective treatments that address the underlying pathophysiological mechanisms of the disease.

Benzydamine attenuates microglia-mediated neuroinflammation and ischemic brain injury by targeting cathepsin s.

Microglia, the primary immune cells of the central nervous system, play a crucial role in the neuroinflammatory processes following ischemic stroke. Targeting neuroinflammation is a promising strategy to enhance the outcomes of ischemic stroke. Benzydamine (BA), a well-known non-steroidal anti-inflammatory drug, has demonstrated potential in inhibiting pro-inflammatory cytokines across various disease models. However, the potential role of BA in microglial activation and post-stroke neuroinflammation remains unclear. Our study reveals that BA effectively suppresses the lipopolysaccharide (LPS)-stimulated pro-inflammatory responses of primary microglia, with high-dose BA (10μM) suppressing LPS-induced inflammatory markers by up to 59.1% in the mRNA levels of IL-1β. Furthermore, BA mitigated ischemic brain injury in experimental stroke mice. BA treatment also significantly attenuated neuroinflammatory responses and attenuates ischemic brain injury in experimental stroke mice. Further investigation revealed that BA reduces the release of the LPS-stimulated pro-inflammatory factors and activation of primary microglia by directly binding to and inhibiting the activity of cathepsin S (CTSS). In conclusion, our study identifies BA as a promising CTSS inhibitor with potential to suppress neuroinflammation following ischemic stroke. Our findings provide a theoretical basis for developing new neuroprotective strategies.

Microglial activation states and their implications for Alzheimer's Disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the accumulation of toxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau protein in the brain. Microglia, key immune cells of the central nervous system, play an important role in AD development and progression, primarily through their responses to Aβ and NFTs. Initially, microglia can clear Aβ, but in AD, chronic activation overwhelms protective mechanisms, leading to sustained neuroinflammation that enhances plaque toxicity, setting off a damaging cycle that affects neurons, astrocytes, cerebral vasculature, and other microglia. Current AD treatments have been largely ineffective, though emerging immunotherapies focusing on plaque removal show promise, but often overlook the role of neuroinflammation. Activated microglia display a complex range of phenotypes that can be broadly broken into pro- or anti-inflammatory states, although this dichotomy does not describe the significant overlap between states. Aβ can strongly induce inflammatory activity, triggering the production of reactive oxygen species, inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), synapse engulfment, blood-brain barrier compromise, and impaired Aβ clearance. These processes contribute to neural tissue loss, manifesting as cognitive decline such as impaired executive function and memory. Conversely, anti-inflammatory activation exerts neuroprotective effects by suppressing inflammatory pathways and releasing neurotrophic factors that aid neuron repair and protection. Induction of anti-inflammatory states may offer a dual therapeutic approach to address both neuroinflammation and plaque accumulation in AD. This approach suggests potential strategies to modulate microglial phenotypes, aiming to restore neuroprotective functions and mitigate disease progression by simultaneously targeting inflammation and plaque pathology.

The Proviral Reservoirs of Human Immunodeficiency Virus (HIV) Infection.

Human Immunodeficiency Virus (HIV) proviral reservoirs are cells that harbor integrated HIV proviral DNA within their nuclear genomes. These cells form a heterogeneous group, represented by peripheral blood mononuclear cells (PBMCs), tissue-resident lymphoid and monocytic cells, and glial cells of the central nervous system. The importance of studying the properties of proviral reservoirs is connected with the inaccessibility of integrated HIV proviral DNA for modern anti-retroviral therapies (ARTs) that block virus reproduction. If treatment is not effective enough or is interrupted, the proviral reservoir can reactivate. Early initiation of ART improves the prognosis of the course of HIV infection, which is explained by the reduction in the proviral reservoir pool observed in the early stages of the disease. Different HIV subtypes present differences in the number of latent reservoirs, as determined by structural and functional differences. Unique signatures of patients with HIV, such as elite controllers, have control over viral replication and can be said to have achieved a functional cure for HIV infection. Uncovering the causes of this phenomenon will bring humanity closer to curing HIV infection, potential approaches to which include stem cell transplantation, clustered regularly interspaced short palindromic repeats (CRISPR)/cas9, "Shock and kill", "Block and lock", and the application of broad-spectrum neutralizing antibodies (bNAbs).