Microglia: Scapegoat, Saboteur, or Something Else?

Aguzzi, Adriano; Barres, Ben A.; Bennett, Mariko L.

doi:10.1126/science.1227901

Cited by 731 publications

(600 citation statements)

References 56 publications

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“…48 We now show that microglia release neurotoxic Ab 1-42 and Ab 1-40 species in association with MVs. This is the first evidence that microglia -which control extracellular plaque load 49,50 by phagocytosis and degradation of Ab fibrils or macropinocytosis of soluble Ab 51,52 -may seed and feed formation of neurotoxic amyloids throughout the brain. MV-mediated release of neurotoxic Ab forms likely occurs when intracellular pathways of Ab degradation are saturated and production of MVs becomes a way for microglia to eliminate undigested Ab.…”

Section: Discussionmentioning

confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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Alzheimer's disease (AD) is characterized by extracellular amyloid-b (Ab) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar Ab species, rather than insoluble fibrils, are the most toxic forms of Ab. Preventing soluble Ab formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble Ab species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic Ab forms trafficked to MVs after Ab internalization into microglia. MV neurotoxicity was neutralized by the Ab-interacting protein PrP and anti-Ab antibodies, which prevented binding to neurons of neurotoxic soluble Ab species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease. Cell Death and Differentiation (2014) 21, 582-593; doi:10.1038/cdd.2013.180; published online 13 December 2013Alzheimer's disease (AD) is the major cause of dementia in humans. Neuronal loss and cognitive decline occurring in AD patients are traditionally linked to the accumulation in the brain of extracellular plaques consisting of short amyloid-b (Ab) peptides of 39-42 amino acids, generated by amyloidogenic cleavage of the amyloid precursor protein. 1 Among Ab peptides, Ab 1-42 and pyroglutamate-modified Ab very rapidly aggregate and initiate the complex multistep process that leads to mature fibrils and plaque. 2,3 Although association of amyloid plaques with AD has long been assumed, Ab load does not correlate with neuronal loss 4,5 and high plaque burden does not necessarily lead to dementia in humans. 6,7 Accordingly, recent evidence clearly showed that the amyloid load reaches a plateau early after the onset of clinical symptoms in AD patients 8 and does not substantially increase in size during clinical progression. 9 These observations agree with the current view that small, soluble pre-fibrillar Ab species, rather than plaques formed by insoluble Ab fibrils, are the most toxic forms of Ab. 10 These cause synaptic dysfunction and spine loss, and correlate most closely with the severity of human AD. 5,8,11 Recent biochemical studies indicated that natural sphingolipids and gangliosides, whose metabolism has been shown to be altered in AD patients, 12 destabilize and rapidly resolubilize long Ab fibrils to neurotoxic species. 13 These studies also showed that phospholipids stabilize toxic oligomers...

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Section: Discussionmentioning

confidence: 99%

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

et al. 2013

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“…purinergic receptors | microglia | blood-brain barrier | stroke | clopidogrel T he resident immune cells of the central nervous system (CNS) play a variety of roles in both CNS development and homeostatic maintenance (1). During development, microglia engulf apoptotic immature neurons and prune synapses to eliminate redundant or inappropriate synaptic connections (2)(3)(4)(5).…”

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confidence: 99%

Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier

Lou

Takano

Pei

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

292

227

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Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition. purinergic receptors | microglia | blood-brain barrier | stroke | clopidogrel

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“…Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig.…”

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confidence: 99%

Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

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Microglia: Scapegoat, Saboteur, or Something Else?

Cited by 731 publications

References 56 publications

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles

Purinergic receptor P2RY12-dependent microglial closure of the injured blood–brain barrier

Age-related myelin degradation burdens the clearance function of microglia during aging

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