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Alzheimer's Research & Therapy Oct 2022Microglia are the resident immune cells found in our brain. They have a critical role in brain maintenance. Microglia constantly scavenge various waste materials in the...
BACKGROUND
Microglia are the resident immune cells found in our brain. They have a critical role in brain maintenance. Microglia constantly scavenge various waste materials in the brain including damaged or apoptotic neurons and Aβ. Through phagocytosis of Aβ, microglia prevent the accumulation of Aβ plaque in the brain. However, in Alzheimer's disease (AD) patients, chronic exposure to Aβ makes microglia to become exhausted, which reduces their phagocytic activity against Aβ. Since microglia play an important role in Aβ clearance, enhancing microglial phagocytic activity against Aβ is a promising target for AD treatment. Therefore, there is a great need for therapeutic candidate that enhances microglial Aβ clearance while inhibiting microglia's pathogenic properties.
METHODS
In vivo studies were conducted with 5xFAD AD model mice by treating gossypetin for 13 weeks through intragastric administration. Their spatial learning and memory were evaluated through behavior tests such as Y-maze and Morris Water Maze test. Hippocampus and cortex were acquired from the sacrificed mice, and they were used for histological and biochemical analysis. Also, mouse tissues were dissociated into single cells for single-cell RNA sequencing (scRNA-seq) analysis. Transcriptome of microglial population was analyzed. Mouse primary microglia and BV2 mouse microglial cell line were cultured and treated with fluorescent recombinant Aβ to evaluate whether their phagocytic activity is affected by gossypetin.
RESULTS
Gossypetin treatment improved the spatial learning and memory of 5xFAD by decreasing Aβ deposition in the hippocampus and cortex of 5xFAD. Gossypetin induced transcriptomic modulations in various microglial subpopulations, including disease-associated microglia. Gossypetin enhanced phagocytic activity of microglia while decreasing their gliosis. Gossypetin also increased MHC II microglial population.
CONCLUSIONS
Gossypetin showed protective effects against AD by enhancing microglial Aβ phagocytosis. Gossypetin appears to be a novel promising therapeutic candidate against AD.
Topics: Animals; Mice; Mice, Transgenic; Spatial Learning; Disease Models, Animal; Alzheimer Disease; Microglia; Phagocytosis; Amyloid beta-Peptides
PubMed: 36271414
DOI: 10.1186/s13195-022-01096-3 -
Nature Neuroscience Dec 2019Although genetics highlights the role of microglia in Alzheimer's disease, one-third of putative Alzheimer's disease risk genes lack adequate mouse orthologs. Here we...
Although genetics highlights the role of microglia in Alzheimer's disease, one-third of putative Alzheimer's disease risk genes lack adequate mouse orthologs. Here we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human-specific Alzheimer's disease risk genes. Oligomeric amyloid-β induces a divergent response in human versus mouse microglia. This model can be used to study the role of microglia in neurological diseases.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Differentiation; Embryonic Stem Cells; Female; Humans; Male; Mice; Mice, Transgenic; Microglia; Transcriptome
PubMed: 31659342
DOI: 10.1038/s41593-019-0525-x -
Seminars in Cell & Developmental Biology Oct 2019
Topics: Animals; Humans; Inflammation; Microglia; Signal Transduction
PubMed: 31299280
DOI: 10.1016/j.semcdb.2019.07.003 -
Biological Reviews of the Cambridge... Feb 2022Microglial cells are the scions of foetal macrophages which invade the neural tube early during embryogenesis. The nervous tissue environment instigates the phenotypic...
Microglial cells are the scions of foetal macrophages which invade the neural tube early during embryogenesis. The nervous tissue environment instigates the phenotypic metamorphosis of foetal macrophages into idiosyncratic surveilling microglia, which are generally characterised by a small cell body and highly ramified motile processes that constantly scan the nervous tissue for signs of changes in homeostasis and allow microglia to perform crucial homeostatic functions. The surveilling microglial phenotype is evolutionarily conserved from early invertebrates to humans. Despite this evolutionary conservation, microglia show substantial heterogeneity in their gene and protein expression, as well as morphological appearance. These differences are age, region and context specific and reflect a high degree of plasticity underlying the life-long adaptation of microglia, supporting the exceptional adaptive capacity of the central nervous system. Microgliocytes are essential elements of cellular network formation and refinement in the developing nervous tissue. Several distinct patrolling modes of microglial processes contribute to the formation, modification, and pruning of synapses; to the support and protection of neurones through microglial-somatic junctions; and to the control of neuronal and axonal excitability by specific microglia-axonal contacts. In pathology, microglia undergo proliferation and reactive remodelling known as microgliosis, which is context dependent, yet represents an evolutionarily conserved defence response. Microgliosis results in the emergence of multiple disease and context-specific reactive states; in addition, neuropathology is associated with the appearance of specific protective or recovery microglial forms. In summary, the plasticity of microglia supports the development and functional activity of healthy nervous tissue and provides highly sophisticated defences against disease.
Topics: Central Nervous System; Microglia; Neurons
PubMed: 34549510
DOI: 10.1111/brv.12797 -
Phytomedicine : International Journal... Oct 2021Magnolol (MA) exhibits anti-depressant effect by inhibiting inflammation. However, its effect on microglia polarization remains not fully understood. Herein, our study...
PURPOSE
Magnolol (MA) exhibits anti-depressant effect by inhibiting inflammation. However, its effect on microglia polarization remains not fully understood. Herein, our study was performed to evaluate the effect of MA on microglia polarization in chronic unpredictable mild stress (CUMS)-induced depression and explore its potential mechanism.
STUDY DESIGN
The CUMS procedure was conducted, and the mice were intragastrically treated with MA. BV2 cells were pretreated with MA prior to LPS/ATP challenge.
METHODS
The levels of TNF-α, IL-1β, IL-6 and IL-4, IL-10 in brain and BV2 cells were examined by ELISA. The mRNA expressions of Arg1, Ym1, Fizz1 and Klf4 in brains were measured. ROS content was determined using flow cytometry. Immunofluorescence was employed to evaluate Iba-1 level, Nrf2 nuclear translocation, Iba-1CD16/32 and Iba-1CD206 cell population. The protein expressions of Nrf2, HO-1, NLRP3, caspase-1 p20 and IL-1β in brains and BV2 cells were investigated by western blot. Nrf2 siRNA was induced in experiments to explore the role of Nrf2 in MA-mediated microglia polarization. The ubiquitination of Nrf2 was visualized by Co-IP.
RESULTS
The treatment with MA notably relieved depressive like behaviors, suppressed pro-inflammatory cytokines, promoted anti-inflammatory cytokines and the transcription of M2 phenotype microglia-specific indicators. MA upregulated the expression of Nrf2, HO-1, downregulated the expression of NLRP3, caspase-1 p20, IL-1β both in vivo and in vitro. MA also reduced ROS concentration, promoted Nrf2 nucleus translocation and prevented Nrf2 ubiquitination. Nrf2 Knockdown by siRNA abolished the MA-mediated microglia polarization.
CONCLUSION
The present research demonstrated that MA attenuated CUMS-stimulated depression by inhibiting M1 polarization and inducing M2 polarization via Nrf2/HO-1/NLRP3 signaling.
Topics: Animals; Biphenyl Compounds; Cell Polarity; Depression; Heme Oxygenase-1; Kruppel-Like Factor 4; Lignans; Lipopolysaccharides; Membrane Proteins; Mice; Microglia; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction
PubMed: 34411834
DOI: 10.1016/j.phymed.2021.153692 -
Human Molecular Genetics Nov 2020Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's...
Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.
Topics: Animals; Animals, Newborn; Gene Expression Regulation; Inflammation; Inflammation Mediators; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Mutation; RNA-Seq; Receptors, Immunologic; STAT6 Transcription Factor; Transcriptome
PubMed: 32959884
DOI: 10.1093/hmg/ddaa209 -
Signal Transduction and Targeted Therapy Feb 2022Neuropsychiatric lupus (NPSLE) is a frequent manifestation of systemic lupus erythematosus (SLE) that occurs in 40-90% of SLE patients; however, the underlying...
Neuropsychiatric lupus (NPSLE) is a frequent manifestation of systemic lupus erythematosus (SLE) that occurs in 40-90% of SLE patients; however, the underlying mechanisms remain elusive, causing a severe lack of therapeutic targets for this condition. Here, we show that complement-coordinated elimination of synapses participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We demonstrated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglial reactivation before overt peripheral lupus pathology. In the lupus brain, C1q was increased and localized at synaptic terminals, causing the apposition of phagocytic microglia and ensuing synaptic engulfment. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition and subsequent microglia-mediated synaptic elimination. Minocycline-mediated deactivation of microglia, antibody blockade of C1q, or neuronal restoration of Nr4a1 protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlighted neuronal Nr4a1 and C1q as critical components amenable to therapeutic intervention in NPSLE.
Topics: Animals; Disease Models, Animal; Lupus Erythematosus, Systemic; Mice; Mice, Inbred MRL lpr; Microglia; Neurons; Nuclear Receptor Subfamily 4, Group A, Member 1
PubMed: 35177587
DOI: 10.1038/s41392-021-00867-y -
Cell Reports Sep 2020Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is...
Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer's disease. Our comparison of microglia from single cells and single nuclei of four human subjects reveals that, although most genes show similar relative abundances in cells and nuclei, a small population of genes (∼1%) is depleted in nuclei compared to whole cells. This population is enriched for genes previously implicated in microglial activation, including APOE, CST3, SPP1, and CD74, comprising 18% of previously identified microglial-disease-associated genes. Given the low sensitivity of snRNA-seq to detect many activation genes, we conclude that snRNA-seq is not suited for detecting cellular activation in microglia in human disease.
Topics: Gene Expression Profiling; Humans; Microglia; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 32997994
DOI: 10.1016/j.celrep.2020.108189 -
Medical Principles and Practice :... 2023Alzheimer's disease (AD) is a disabling neurodegenerative disease. The prognosis is poor, and currently there are no proven effective therapies. Most likely, the... (Review)
Review
Alzheimer's disease (AD) is a disabling neurodegenerative disease. The prognosis is poor, and currently there are no proven effective therapies. Most likely, the etiology is related to cerebral inflammatory processes that cause neuronal damage, resulting in dysfunction and apoptosis of nerve cells. Pathogens that evoke a neuroinflammatory response, collectively activate astrocytes and microglia, which contributes to the secretion of pro-inflammatory cytokines. This leads to the deposit of clustered fragments of beta-amyloid and misfolded tau proteins which do not elicit an adequate immune reaction. Apart from the function of astrocytes and microglia, molecular entities such as TREM2, SYK, C22, and C33 play a role in the physiopathology of AD. Furthermore, bacteria and viruses may trigger an overactive inflammatory response in the brain. Pathogens like Helicobacter pylori, Chlamydia pneumonia, and Porphyromonas gingivalis (known for low-grade infection in the oral cavity) can release gingipains, which are enzymes that can damage and destroy neurons. Chronic infection with Borrelia burgdorferi (the causative agent of Lyme disease) can co-localize with tau tangles and amyloid deposits. As for viral infections, herpes simplex virus 1, cytomegalovirus, and Epstein-Barr virus can play a role in the pathogenesis of AD. Present investigations have resulted in the development of antibodies that can clear the brain of beta-amyloid plaques. Trials with humanized aducanumab, lecanemab, and donanemab revealed limited success in AD patients. However, AD should be considered as a continuum in which the initial preclinical phase may take 10 or even 20 years. It is generally thought that this phase offers a window for efficacious treatment. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots.
Topics: Humans; Alzheimer Disease; Epstein-Barr Virus Infections; Neurodegenerative Diseases; Herpesvirus 4, Human; Amyloid beta-Peptides; Microglia
PubMed: 37788649
DOI: 10.1159/000534400 -
Development (Cambridge, England) Apr 2022It has recently emerged that microglia, the tissue-resident macrophages of the central nervous system, play significant non-innate immune roles to support the... (Review)
Review
It has recently emerged that microglia, the tissue-resident macrophages of the central nervous system, play significant non-innate immune roles to support the development, maintenance, homeostasis and repair of the brain. Apart from being highly specialized brain phagocytes, microglia modulate the development and functions of neurons and glial cells through both direct and indirect interactions. Thus, recognizing the elements that influence the homeostasis and heterogeneity of microglia in normal brain development is crucial to understanding the mechanisms that lead to early disease pathogenesis of neurodevelopmental disorders. In this Review, we discuss recent studies that have elucidated the physiological development of microglia and summarize our knowledge of their non-innate immune functions in brain development and tissue repair.
Topics: Brain; Central Nervous System; Homeostasis; Microglia; Neuroglia
PubMed: 35502782
DOI: 10.1242/dev.200425