MFG-E8 Regulates Microglial Phagocytosis of Apoptotic Neurons

Fuller, Abby D.; Eldik, Linda J. Van

doi:10.1007/s11481-008-9118-2

Cited by 123 publications

(118 citation statements)

References 45 publications

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“…We also analyzed the levels of MFG‐E8, a molecule that has been shown to mediate microglia phagocytosis 45. Despite the fact that MFG‐E8 was increased in AD cases compared to both FTLD subtypes, it did not discriminate those clinical groups.…”

Section: Discussionmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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Section: Discussionmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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“…(Fig. 3 B), and the microglial cell line BV-2 was reported to express Mfge8 (Fuller and Van Eldik, 2008). Because explanted microglia tend to dedifferentiate and to become activated, we wondered whether microglia up-regulate Mfge8 expression upon activation.…”

Section: Astrocytes Express Mfge8mentioning

confidence: 98%

“…Human and mouse astrocytes, microglia, and smooth muscle cells (Boddaert et al, 2007;Fuller and Van Eldik, , and Gfap expression in cerebellar slice cultures from untreated CD11b-HSVTK mice (HSVTK), prion-inoculated untreated CD11b-HSVTK mice (HSVTK + RML), GCV-treated CD11b-HSVTK mice (HSVTK + GCV), and prion-inoculated GCV-treated CD11b-HSVTK mice (HSVTK + RML + GCV; Student's t test; n = 4). Uninfected HSVTK + GCV slices compared with HSVTK slices have a slight but significant reduction of Mfge8 (***, P = 0.0007).…”

Section: Astrocytes Express Mfge8mentioning

confidence: 99%

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Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner

Kranich¹,

Kräutler²,

Falsig³

et al. 2010

J Cell Biol

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Progressive accumulation of PrP(Sc), a hallmark of prion diseases, occurs when conversion of PrP(C) into PrP(Sc) is faster than PrP(Sc) clearance. Engulfment of apoptotic bodies by phagocytes is mediated by Mfge8 (milk fat globule epidermal growth factor 8). In this study, we show that brain Mfge8 is primarily produced by astrocytes. Mfge8 ablation induced accelerated prion disease and reduced clearance of cerebellar apoptotic bodies in vivo, as well as excessive PrP(Sc) accumulation and increased prion titers in prion-infected C57BL/6 × 129Sv mice and organotypic cerebellar slices derived therefrom. These phenotypes correlated with the presence of 129Sv genomic markers in hybrid mice and were not observed in inbred C57BL/6 Mfge8(-/-) mice, suggesting the existence of additional strain-specific genetic modifiers. Because Mfge8 receptors are expressed by microglia and depletion of microglia increases PrP(Sc) accumulation in organotypic cerebellar slices, we conclude that engulfment of apoptotic bodies by microglia may be an important pathway of prion clearance controlled by astrocyte-borne Mfge8.

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“…Phagocytic PS recognition can be mediated by so-called bridging proteins, including MFG-E8 (21). MFG-E8 is a secreted glycoprotein that binds exposed PS through its C1 and C2 domains, and the macrophage vitronectin receptor through an RGD motif, thus bridging the phagocyte and the target cell (10,22).…”

Section: Inhibition Of Phagocytosis Prevents Lta- Lps- and Peroxynimentioning

confidence: 99%

Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

Neher

Neniskyte

Zhao

et al. 2011

The Journal of Immunology

331

399

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It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain’s macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of ∼30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging.

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MFG-E8 Regulates Microglial Phagocytosis of Apoptotic Neurons

Cited by 123 publications

References 45 publications

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner

Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

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