The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice

Xin, Ying; Jiang, Jie; Hu, Yang; Jiang, Pan; Mi, Xiang-Nan; Gao, Qin; Xiao, Fei; Zhang, Wei; Luo, Hongyu

doi:10.3389/fnagi.2019.00279

Cited by 49 publications

(33 citation statements)

References 37 publications

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“…Intraperitoneal administration of LPS (10 mg/kg) for 7 days induces marked upregulation of C1q and C3 by activating the classical complement pathway, microglial activation, synapse loss in the hippocampus, and cognitive deficits in Kunming mice (125). Repeated intraperitoneal administration of LPS (1 mg/kg/day for 4 consecutive days) induces dopaminergic neuron loss in the substantia nigra in mice but a single LPS injection does not.…”

Section: Role Of Complement In Systemic Inflammation In Neurodegeneramentioning

confidence: 98%

“…Repeated intraperitoneal injection of LPS activated microglia and increased tau phosphorylation in an AD mouse model (3xTg-AD) (124). Daily intraperitoneal LPS injection in Kunming mice for 7 days induced microglia activation, upregulation of proinflammatory cytokines (both mRNA and protein) including IL-1β, TNF-α, and IL-6, synapse loss, and impairment of learning and memory (125). Acute intraperitoneal LPS injection also increased tau phosphorylation in the hippocampal neurons of C57BL/6 mice (126,127).…”

Section: Role Of Tlr4 Signaling In Systemic Inflammation In Alzheimermentioning

confidence: 99%

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TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

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Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

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Section: Role Of Complement In Systemic Inflammation In Neurodegeneramentioning

confidence: 98%

Section: Role Of Tlr4 Signaling In Systemic Inflammation In Alzheimermentioning

confidence: 99%

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

2020

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“…However, low-grade systemic inflammation in GFP AAV9 brains did not influence brain weight or neuronal count, suggesting that TDP-43 altered the susceptibility of the brain to the systemic inflammatory response. Next, since both TDP-43 [ 37 – 39 ] and LPS-mediated [ 40 – 42 ] neuroinflammation can alter the expression of synaptic markers that can lead to cognitive decline, we performed western blotting of several synaptic markers as a measure of synaptic dysfunction in frontal cortex lysates. While PSD95, synaptophysin, syntaxin 1-A, and SNAP-23 protein levels remain unaltered by TDP-43 overexpression alone or low-grade systemic inflammation, SNAP-25 expression levels were reduced by half in the brains of LPS-treated TDP-43 AAV9 mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Zamudio

Loon

Smeltzer

et al. 2020

J Neuroinflammation

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Background Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases. Methods To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 μg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue. Results In the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task. Conclusions These results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.

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“…Then, mice should be treated with lipopolysaccharide (LPS), either locally or systemically, to induce robust pro-inflammatory microglial activation. Of note, LPS has previously been shown to induce microglial-mediated synapse loss [ 58 ], and since microglia make up a significant portion of glioma [ 59 ], treatment with a pro-inflammatory mediator, such as LPS, should quickly reveal whether microglia have the potential to perturb or destroy these aberrant synapses. If promoting pro-inflammatory microglial activation is sufficient to curb oncogenic interaction between neurons and glioma cells, further translational studies with safer drugs, such as the FDA-approved antifungal Amphotericin B, may be worth pursuing [ 60 ].…”

Section: Microglia: Potential Role As Synaptic Sculptors?mentioning

confidence: 99%

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

Radin

Tsirka

2020

IJMS

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Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy.

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The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice

Cited by 49 publications

References 37 publications

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

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