Microglial phagocytosis of live neurons

Brown, Guy C.; Neher, Jonas J.

doi:10.1038/nrn3710

Cited by 734 publications

(706 citation statements)

References 75 publications

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“…Damage to the neuron ultimately arises from the combination of altered microglial function and the specific chemical environment. Our findings are in line with recent observations that microglial engulfment of live neurons plays a significant role in neurodegenerative diseases 24, 25…”

Section: Discussionsupporting

confidence: 93%

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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ObjectiveMutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.MethodsWe assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very‐long‐chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.ResultsWithin the spinal cord of humans and mice with AMN, upregulation of several phagocytosis‐related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1‐deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8‐blocking antibody reduces phagocytic activity.InterpretationSpinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813–827

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Section: Discussionsupporting

confidence: 93%

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Gong

Sasidharan

Laheji

et al. 2017

Annals of Neurology

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“…Neuronal dendritic spine densities and connections are elevated during brain development. These synapses are subsequently pruned and the neuronal circuits sculpted/refined by the appearance and proliferation of microglia during key critical periods (Brown & Neher, 2014; Kettenmann et al, 2013; Paolicelli et al, 2011). Evidence for the importance of microglia‐mediated synaptic pruning and refining during development comes from observations that transgenic mice with perturbed microglial function have impaired cognitive function and synaptic plasticity (Rogers et al, 2011), decreased synaptic pruning, and display autistic‐like phenotypes (Zhan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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“…Microglia and astrocytes have received considerable attention recently due to their contributions to a wide array of homeostatic and non-inflammatory processes, as well as during states of heightened inflammation and injury (Brown and Neher, 2014;Ginhoux and Jung, 2014;Prinz and Priller, 2014;Salter and Beggs, 2014;Walsh et al, 2014). Glial and neuroimmune mechanisms have been extensively characterized in the context of pathological pain (Grace et al, 2014a), while researchers attempting to decode the complex etiology of neurodegenerative disorders such as Alzheimer's disease have also argued for a more holistic framework, where the interactions and compensatory responses between neurons, glia, and vascular cells all contribute to the progression of the disease (De Strooper and Karran, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…In turn, glial responses to drugs of abuse could influence neuronal function directly through physical remodeling of structural components (Brown and Neher, 2014;Corty and Freeman, 2013), as described in the previous section, or indirectly through a variety of released compounds (see Block et al, 2007). This chemical communication from glia can be both anti-inflammatory and neuroprotective (eg, IL-10, TGF-β, and BDNF) or proinflammatory and neurotoxic (eg, IL-1β, TNFα, and NADPH oxidase) (see Figure 1).…”

Section: Opioids Glia and Neuroimmune Signalingmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Microglial phagocytosis of live neurons

Cited by 734 publications

References 75 publications

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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