Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity

Nguyen, Phi T.; Dorman, Leah C.; Pan, Simon; Vainchtein, Ilia D.; Han, Rafael Taeho; Nakao-Inoue, Hiromi; Taloma, Sunrae; Barron, Jerika J.; Molofsky, Ari B.; Kheirbek, Mazen A.; Molofsky, Anna V.

doi:10.1016/j.cell.2020.05.050

Cited by 376 publications

(395 citation statements)

References 108 publications

(116 reference statements)

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“…We found the top enriched pathways were related to ECM, including those associated with chondroitin/dermatan sulfate metabolism (Figure 2f). Intriguingly, our data suggests links between ECM remodeling, microglial cell migration, and synaptic plasticity, in line with recent work (40). Specifically, we discovered enrichment of pathways in synapse organization (Figure 2f, Figure S3).…”

Section: Enrichment Of Differentially Expressed Transcripts Involved supporting

confidence: 91%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, we still have a very limited understanding of the biological changes that occur in the brains of people who chronically use opioids and who are diagnosed with OUD. To address this, we conducted the largest transcriptomics study to date using postmortem brains from subjects with OUD. We focused on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), two regions heavily implicated in OUD. We discovered a high degree of overlap in transcripts between DLPFC and NAc in OUD, primarily associated with neuroinflammation. Moreover, additional transcripts were enriched for factors that control pro-inflammatory cytokine-mediated signaling and remodeling of the extracellular matrix (ECM). Our results also implicate a role for microglia as a critical driver for opioid-induced neuroplasticity. Overall, our findings reveal new connections between the brain’s immune system and opioid dependence in the human brain.

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Section: Enrichment Of Differentially Expressed Transcripts Involved supporting

confidence: 91%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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“…It is interesting to note that we identified here and elsewhere [36] a homeostatic role for microglia in the maintenance of PNNs, such that basal PNN levels in the healthy adult brain are elevated following microglial depletion. Recent work in mice shows that microglial clearance of ECM in response to neuronal IL-33 promotes synaptic remodeling and plasticity [89] . Importantly, inhibiting this pathway results in reduced microglial phagocytosis and engulfment of ECM components (e.g.…”

Section: Discussionmentioning

confidence: 99%

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

et al. 2020

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Background Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial. Methods Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia. Findings Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence. Interpretation We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain. Funding The NIH (NIA, NINDS) and the Alzheimer's Association.

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“…In addition to their immune functions, microglia crucially support brain development, for example, by sculpting neuronal synapses in the developing brain. In the adult brain, microglia perform multiple functions, including monitoring changes in neuronal activity, modulating learning and memory, and acting as local phagocytes and damage sensors in the brain parenchyma (6)(7)(8)(9)(10)(11)(12).…”

Section: Microglia Are Central To Neuronal Function and Healthmentioning

confidence: 99%

Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases

Bartels

Schepper

Hong

2020

Science

257

162

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Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer’s and Parkinson’s diseases. Understanding how to assess and modulate microglia-neuron interactions critical for brain health will be key to developing effective therapies for dementia.

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Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity

Cited by 376 publications

References 108 publications

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases

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