Evidence of a Role for Lactadherin in Alzheimer's Disease

Boddaert, Jacques; Kinugawa, Kiyoka; Lambert, Jean‐Charles; Boukhtouche, Fatiha; Zoll, Joffrey; Merval, Régine; Blanc‐Brude, Olivier; Mann, David; Berr, Claudine; Vilar, José; Garabedian, Béatrice Vernet-der; Journiac, Nathalie; Charue, Dominique; Silvestre, Jean‐Sébastien; Duyckaerts, Charles; Amouyel, Philippe; Mariani, Jean; Tedgui, Alain; Mallat, Ziad

doi:10.2353/ajpath.2007.060664

Cited by 92 publications

(98 citation statements)

References 60 publications

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“…It is also involved in the VEGF-dependent neovascularization (31) and in the migration of enterocytes and intestinal repair (32). It has been proposed to be beneficial in atherosclerosis (33) and Alzheimer's disease (34), although the mechanism is still unclear. MFG-E8 plays an important role at the interface between phagocytosis of apoptotic cells and inflammation in chronic and acute inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

Cui

Miksa

et al. 2010

Am J Respir Crit Care Med

116

110

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Rationale: Milk fat globule epidermal growth factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. It attenuates chronic and acute inflammation such as autoimmune glomerulonephritis and bacterial sepsis by enhancing apoptotic cell clearance. Ischemia-reperfusion (I/R) injury of the gut results in severe inflammation, apoptosis, and remote organ damage, including acute lung injury (ALI). Objectives: To determine whether MFG-E8 attenuates intestinal and pulmonary inflammation after gut I/R. Methods: Wild-type (WT) and MFG-E8 2/2 mice underwent superior mesenteric artery occlusion for 90 minutes, followed by reperfusion for 4 hours. A group of WT mice was treated with 0.4 mg/20 g recombinant murine MFG-E8 (rmMFG-E8) at the beginning of reperfusion. Four hours after reperfusion, MFG-E8, cytokines, myeloperoxidase activity, apoptosis, and histopathology were assessed. A 24-hour survival study was conducted in rmMFG-E8-and vehicletreated WT mice. Measurements and Main Results: Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, including the lungs. MFG-E8 levels decreased in the spleen and lungs by 50 to 60%, suggesting impaired apoptotic cell clearance. Treatment with rmMFG-E8 significantly suppressed inflammation (TNF-a, IL-6, IL-1b, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment with rmMFG-E8 significantly improved the survival in WT mice. Conclusions: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

Cui

Miksa

et al. 2010

Am J Respir Crit Care Med

116

110

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“…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%

“…Mfge8 is secreted by some phagocytic cells, including immature DCs and thioglycolate-activated peritoneal macrophages, as well as nonhematopoietic cells, including mammary epithelial cells (Hanayama and Nagata, 2005) and follicular DCs (FDCs; Kranich et al, 2008). A recent study described a potential involvement of Mfge8 expressed by human astrocytes, microglia, and smooth muscle cells in the removal of A plaques (Boddaert et al, 2007). A microarray screen also identified Mfge8 expression in mouse astrocytes (Cahoy et al, 2008).…”

mentioning

confidence: 99%

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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“…Semi- quantitative analyses of AIF immunostaining were performed by W.Y. in a blind fashion and were based on the following scoring criteria 31,32 : A score of 0 was assigned to samples in which AIF expression was undetectable, whereas 1, 2, and 3 were assigned to samples with low, moderate, and strong immunostaining, respectively. For AIF immunostaining extent, 0, 1, 2, 3, and 4 was assigned to samples as 0 to 5%, 6 to 25%, 26 to 50%, 51% to 75%, and 76% to 100% of the neuronal population, respectively.…”

Section: Quantification Of Aif-immunoreactive Neurons In Hippocampus mentioning

confidence: 99%

Evidence for the Involvement of Apoptosis-Inducing Factor–Mediated Caspase-Independent Neuronal Death in Alzheimer Disease

Mechawar

Krantic

et al. 2010

The American Journal of Pathology

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Accumulating evidence suggests the involvement of caspase-dependent and -independent mechanisms in neuronal cell death in Alzheimer disease (AD). The apoptosis-inducing factor (AIF) is a mitochondrial oxido-reductase originally characterized as a mediator of caspase-independent programmed cell death (PCD). In this postmortem study, we investigated the distribution of AIF and its possible morphological association with pathological features in the hippocampus, as well as entorhinal and medial gyrus of temporal cortices of late stage AD, dementia with Lewy bodies (DLB), and control subjects. In comparison with controls, a significant increase in neuronal AIF immunoreactivity (AIF-ir) was observed in the hippocampus and the superficial layers of entorhinal and medial gyrus of temporal cortices in AD-but not DLB-samples. AIF-ir in neuronal nuclei was also significantly more widespread in AD compared with control and DLB samples. Furthermore, AIF-ir was found to be colocalized with neurofibrillary tangles (NFTs) in AD brains. Interestingly, a significant positive correlation was seen between nuclear AIF-ir and Braak stage in CA1 of the hippocampus as well as in entorhinal and temporal cortices in AD samples. These data show for the first time: (1) the nuclear localization of AIF in the AD brain and (2) its colocalization with NFTs, suggesting a possible involvement of AIF-mediated caspase-independent PCD, at least in the late stage of this neuropathology. (Am J Pathol

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Evidence of a Role for Lactadherin in Alzheimer's Disease

Cited by 92 publications

References 60 publications

Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

Milk Fat Globule Epidermal Growth Factor 8 Attenuates Acute Lung Injury in Mice after Intestinal Ischemia and Reperfusion

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

Evidence for the Involvement of Apoptosis-Inducing Factor–Mediated Caspase-Independent Neuronal Death in Alzheimer Disease

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