Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions

Neuron, Journal Year: 2020, Volume and Issue: 109(2), P. 222 - 240

Published: Dec. 2, 2020

Language: Английский

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Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: March 22, 2021

Abstract Background Recent studies suggest that microglia contribute to tau pathology progression in Alzheimer’s disease. Amyloid plaque accumulation transforms microglia, the primary innate immune cells brain, into neurodegenerative (MGnD), which exhibit enhanced phagocytosis of plaques, apoptotic neurons and dystrophic neurites containing aggregated phosphorylated (p-tau). It remains unclear how promote disease while actively phagocytosing pathological proteins, therefore ameliorating pathology. Methods Adeno-associated virus expressing P301L mutant (AAV-P301L-tau) was stereotaxically injected medial entorhinal cortex (MEC) C57BL/6 (WT) humanized APP knock-in homozygote ( App NL-G-F ) mice at 5 months age. Mice were fed either chow a colony stimulating factor-1 receptor inhibitor (PLX5622) or control from 4 6 age test effect depletion. Animals tested for immunofluorescence, biochemistry, FACS microglia. In order monitor microglial extracellular vesicle secretion vivo, novel lentiviral EV reporter system engineered express mEmerald-CD9 (mE-CD9) specifically same region MEC. Results Expressing MEC induced propagation granule cell layer hippocampal dentate gyrus, significantly exacerbated compared WT mice. Administration PLX5622 depleted nearly all mouse brains dramatically reduced p-tau greater extent mice, although it increased burden plaque-associated + neurites. Plaque-associated MGnD strongly expressed an marker, tumor susceptibility gene 101, indicative heightened synthesis EVs. Intracortical injection mE-CD9 lentivirus successfully microglia-specific expression particles, Mac2 − homeostatic Finally, consecutive intracortical AAV-P301L-tau revealed encapsulation EVs as determined by super-resolution microscopy immuno-electron microscopy. Discussion Our findings hyper-secrete compacting Aβ plaques clearing NP tau, we propose mechanistic link between amyloid deposition exacerbation

Language: Английский

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Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models

Nature Aging, Journal Year: 2022, Volume and Issue: 2(9), P. 837 - 850

Published: Sept. 20, 2022

Abstract Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic microglial proteins are increased Tau P301S synapse fractions with age a C1q-dependent manner. In addition to microglia, identified astrocytes contribute substantially elimination hippocampi. Notably, found relatively more excitatory marker lysosomes, whereas lysosomes contained inhibitory material. C1q deletion reduced astrocyte–synapse association decreased synapses engulfment mice rescued density. Finally, an AD mouse model combines β-amyloid pathologies, of the risk gene Trem2 impaired phagocytosis synapses, engulfed around plaques. Together, our data reveal contact eliminate manner thereby pathological loss compensate for dysfunction.

Language: Английский

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Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques

Immunity, Journal Year: 2022, Volume and Issue: 55(5), P. 879 - 894.e6

Published: April 19, 2022

Language: Английский

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Microglia regulate synaptic development and plasticity

Developmental Neurobiology, Journal Year: 2021, Volume and Issue: 81(5), P. 568 - 590

Published: Feb. 14, 2021

Synapses are fundamental structures of neural circuits that transmit information between neurons. Thus, the process circuit formation via proper synaptic connections shapes basis brain functions and animal behavior. continuously undergo repeated elimination throughout lifetime an organism, reflecting dynamics function. The structural transformation synapses has been described mainly in relation to activity-dependent strengthening weakening functions, is, functional plasticity synapses. An increasing number studies have unveiled roles microglia, brain-resident immune cells survey parenchyma with highly motile processes, synapse as well regulating Over past 15 years, molecular mechanisms underlying microglia-dependent regulation thoroughly studied, researchers reported disruption causes dysfunction leads diseases. In this review, we will broadly introduce report microglia possible mechanisms.

Language: Английский

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Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(8), P. 576 - 596

Published: April 27, 2023

Language: Английский

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Cerebral dysfunctions caused by sepsis during ageing

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 22(7), P. 444 - 458

Published: Nov. 11, 2021

Language: Английский

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Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

Cell Reports, Journal Year: 2022, Volume and Issue: 38(13), P. 110600 - 110600

Published: March 1, 2022

Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation microglia increased reduced density to control levels. Notably, normalized adult acute responses, including stress-induced secretion behavioral threat as well adrenal hypertrophy mice. Thus, actions during development are powerful contributors mechanisms which sculpts connectivity stress-regulating promoting vulnerability illnesses.

Language: Английский

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Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates

Science Advances, Journal Year: 2021, Volume and Issue: 7(43)

Published: Oct. 21, 2021

The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that phagocytose live neurons containing cultured from P301S mice due to neuronal aggregate-induced exposure “eat me” signal phosphatidylserine. Here, we show after phagocytosing aggregate-bearing neurons, become hypophagocytic while releasing seed-competent insoluble aggregates. These express a senescence-like phenotype, demonstrated acidic β-galactosidase activity, secretion paracrine senescence-associated cytokines, maturation matrix remodeling enzymes, results are corroborated mouse brains ex vivo brain slices. In particular, nuclear factor κB–dependent activation metalloprotease 3 (MMP3/stromelysin1) was replicated patients with tauopathy. data been activated ingest aggregates-bearing behave hormetically, becoming hypofunctional acting as vectors aggregate spreading.

Language: Английский

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Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(11), P. 2472 - 2488

Published: Aug. 19, 2021

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist a vacuum. Instead, pre- postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise four elements of contemporary tetrapartite synapse model. While research this area is still just beginning, accumulating evidence points toward novel role for microglia regulating ECM during normal brain homeostasis, such processes may, turn, become dysfunctional disease. As it relates to synapses, reported modify perisynaptic matrix, diffuse that surrounds dendritic axonal terminals, as well perineuronal nets (PNNs), specialized reticular formations compact enwrap neuronal subsets stabilize proximal synapses. The interconnected relationship between they embedded suggests alterations one structure necessarily affect dynamics other, may need sculpt within. Here, we provide an overview microglial regulation PNNs, propose candidate mechanisms these structures be modified, present implications modifications homeostasis

Language: Английский

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