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Experimental Neurology Oct 2021Methamphetamine (METH) is an illicit psychostimulant that is abused throughout the world. METH addiction is also a major public health concern and the abuse of large... (Review)
Review
Methamphetamine (METH) is an illicit psychostimulant that is abused throughout the world. METH addiction is also a major public health concern and the abuse of large doses of the drug is often associated with serious neuropsychiatric consequences that may include agitation, anxiety, hallucinations, paranoia, and psychosis. Some human methamphetamine users can also suffer from attention, memory, and executive deficits. METH-associated neurological and psychiatric complications might be related, in part, to METH-induced neurotoxic effects. Those include altered dopaminergic and serotonergic functions, neuronal apoptosis, astrocytosis, and microgliosis. Here we have endeavored to discuss some of the main effects of the drug and have presented the evidence supporting certain of the molecular and cellular bases of METH neurotoxicity. The accumulated evidence suggests the involvement of transcription factors, activation of dealth pathways that emanate from mitochondria and endoplasmic reticulum (ER), and a role for neuroinflammatory mechanisms. Understanding the molecular processes involved in METH induced neurotoxicity should help in developing better therapeutic approaches that might also serve to attenuate or block the biological consequences of use of large doses of the drug by some humans who meet criteria for METH use disorder.
Topics: Animals; Brain; Central Nervous System Stimulants; Humans; Methamphetamine; Neurotoxicity Syndromes
PubMed: 34186102
DOI: 10.1016/j.expneurol.2021.113795 -
Neuron Feb 2007Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we...
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.
Topics: Aging; Amygdala; Amyloid Neuropathies; Animals; Atrophy; Blotting, Western; Brain; Gliosis; Humans; Immunohistochemistry; Immunosuppressive Agents; Macrophage Activation; Mice; Microglia; Microscopy, Electron; Microtubules; Mossy Fibers, Hippocampal; Nerve Degeneration; Neurofibrillary Tangles; Phosphorylation; Solubility; Spinal Cord; Synapses; Tacrolimus; tau Proteins
PubMed: 17270732
DOI: 10.1016/j.neuron.2007.01.010 -
Neuron Dec 2018The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic... (Review)
Review
The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions. We also reveal an emerging role of microglia in the resolution of pain, in part via specialized pro-resolving mediators including resolvins, protectins, and maresins. We also discuss a possible role of microglia in chronic itch.
Topics: Animals; Central Nervous System; Cytokines; Humans; Inflammation; Microglia; Pain; Pain Management; Signal Transduction; Up-Regulation
PubMed: 30571942
DOI: 10.1016/j.neuron.2018.11.009 -
Neuron Jan 2023In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates...
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.
Topics: Mice; Animals; Apolipoprotein E4; Alzheimer Disease; Inflammation; Microglia; Disease Models, Animal; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 36368315
DOI: 10.1016/j.neuron.2022.10.022 -
Inflammopharmacology Jun 2023Nociplastic pain is the third classification of pain as described by the International Association for the Study of Pain (IASP), in addition to the neuropathic and... (Review)
Review
Nociplastic pain is the third classification of pain as described by the International Association for the Study of Pain (IASP), in addition to the neuropathic and nociceptive pain classes. The main pathophysiological mechanism for developing nociplastic pain is central sensitization (CS) in which pain amplification and hypersensitivity occur. Fibromyalgia is the prototypical nociplastic pain disorder, characterized by allodynia and hyperalgesia. Much scientific data suggest that classical activation of microglia in the spinal cord mediates neuroinflammation which plays an essential role in developing CS. In this review article, we discuss the impact of microglia activation and M1/M2 polarization on developing neuroinflammation and nociplastic pain, besides the molecular mechanisms engaged in this process. In addition, we mention the impact of microglial modulators on M1/M2 microglial polarization that offers a novel therapeutic alternative for the management of nociplastic pain disorders. Illustrating the mechanisms underlying microglia activation in central sensitization and nociplastic pain. LPS lipopolysaccharide, TNF-α tumor necrosis factor-α, INF-γ Interferon gamma, ATP adenosine triphosphate, 49 P2Y12/13R purinergic P2Y 12/13 receptor, P2X4/7R purinergic P2X 4/7 receptor, SP Substance P, NK-1R Neurokinin 1 receptor, CCL2 CC motif ligand 2, CCR2 CC motif ligand 2 receptor, CSF-1 colony-stimulating factor 1, CSF-1R colony-stimulating factor 1 receptor, CX3CL1 CX3C motif ligand 1, CX3XR1 CX3C motif ligand 1 receptor, TLR toll-like receptor, MAPK mitogen-activated protein kinases, JNK jun N-terminal kinase, ERK extracellular signal-regulated kinase, iNOS Inducible nitric oxide synthase, IL-1β interleukin-1β, IL-6 interleukin-6, BDNF brain-derived neurotrophic factor, GABA γ-Aminobutyric acid, GABAR γ-Aminobutyric acid receptor, NMDAR N-methyl-D-aspartate receptor, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropi-onic acid receptor, IL-4 interleukin-4, IL-13 interleukin-13, IL-10 interleukin-10, Arg-1 Arginase 1, FGF fibroblast growth factor, GDNF glial cell-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, NGF nerve growth factor, CD Cluster of differentiation.
Topics: Humans; Microglia; Macrophage Colony-Stimulating Factor; Neuroinflammatory Diseases; Ligands; Pain; Hyperalgesia; Interleukin-6; Lipopolysaccharides; Tumor Necrosis Factor-alpha
PubMed: 37069462
DOI: 10.1007/s10787-023-01216-x -
Current Neuropharmacology 2021Neurological disorders (ND) are the central nervous system (CNS) related complications originated by enhanced oxidative stress, mitochondrial failure and overexpression... (Review)
Review
Neurological disorders (ND) are the central nervous system (CNS) related complications originated by enhanced oxidative stress, mitochondrial failure and overexpression of proteins like S100B. S100B is a helix-loop-helix protein with the calcium-binding domain associated with various neurological disorders through activation of the MAPK pathway, increased NF-kB expression resulting in cell survival, proliferation and gene up-regulation. S100B protein plays a crucial role in Alzheimer's disease, Parkinson's disease, multiple sclerosis, Schizophrenia and epilepsy because the high expression of this protein directly targets astrocytes and promotes neuroinflammation. Under stressful conditions, S100B produces toxic effects mediated through receptor for advanced glycation end products (AGE) binding. S100B also mediates neuroprotection, minimizes microgliosis and reduces the expression of tumor necrosis factor (TNF-alpha) but that are concentration- dependent mechanisms. Increased level of S100B is useful for assessing the release of inflammatory markers, nitric oxide and excitotoxicity dependent neuronal loss. The present review summarizes the role of S100B in various neurological disorders and potential therapeutic measures to reduce the prevalence of neurological disorders.
Topics: Astrocytes; Biomarkers; Humans; Nervous System Diseases; Parkinson Disease; S100 Calcium Binding Protein beta Subunit
PubMed: 32727332
DOI: 10.2174/1570159X18666200729100427 -
Acta Neuropathologica Apr 2023Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in...
Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ, S100 calcium-binding protein B macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.
Topics: Male; Humans; Female; Alzheimer Disease; Amyloid beta-Peptides; Proteome; Proteomics; Retina; Atrophy; Biomarkers
PubMed: 36773106
DOI: 10.1007/s00401-023-02548-2 -
Cell Reports Mar 2023Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood....
Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
Topics: Humans; Animals; Mice; COVID-19; Spike Glycoprotein, Coronavirus; SARS-CoV-2; Toll-Like Receptor 4; Post-Acute COVID-19 Syndrome; Cognitive Dysfunction
PubMed: 36857178
DOI: 10.1016/j.celrep.2023.112189 -
Glia Jun 2021Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The...
Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival-is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events.
Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Macrophages; Mice; Microglia; Receptors, Colony-Stimulating Factor; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Signal Transduction
PubMed: 33620118
DOI: 10.1002/glia.23980 -
Proceedings of the National Academy of... Feb 2023Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Upon pathological...
Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Upon pathological stimulation, microglia are converted from a surveillant to an overactivated phenotype. However, the molecular characters of proliferating microglia and their contributions to the pathogenesis of neurodegeneration remain unclear. Here, we identify chondroitin sulfate proteoglycan 4 ( also known as neural/glial antigen 2)-expressing microglia as a specific subset of microglia with proliferative capability during neurodegeneration. We found that the percentage of microglia was increased in mouse models of PD. The transcriptomic analysis of microglia revealed that the subcluster microglia displayed a unique transcriptomic signature, which was characterized by the enrichment of orthologous cell cycle genes and a lower expression of genes responsible for neuroinflammation and phagocytosis. Their gene signatures were also distinct from that of known disease-associated microglia. The proliferation of quiescent microglia was evoked by pathological α-synuclein. Following the transplantation in the adult brain with the depletion of endogenous microglia, microglia grafts showed higher survival rates than their counterparts. Consistently, microglia were detected in the brain of AD patients and displayed the expansion in animal models of AD. These findings suggest that microglia are one of the origins of microgliosis during neurodegeneration and may open up a avenue for the treatment of neurodegenerative diseases.
Topics: Mice; Animals; Microglia; Parkinson Disease; Alzheimer Disease; Neurodegenerative Diseases; Phagocytosis
PubMed: 36795751
DOI: 10.1073/pnas.2210643120