MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy

Marazuela, Paula; Solé, Montse; Bonaterra-Pastra, Anna; Pizarro, Jesús; Camacho, Jessica; Martínez‐Sáez, Elena; Kuiperij, H. Bea; Verbeek, Marcel M.; Kort, Anna M. de; Schreuder, Floris H.B.M.; Klijn, Catharina J.M.; Castillo-Ribelles, Laura; Pancorbo, Olalla; Rodríguez‐Luna, David; Pujadas, Francesc; Delgado, Pilar; Hernández-Guillamón, Mar

doi:10.1186/s40478-021-01257-9

Cited by 12 publications

(8 citation statements)

References 79 publications

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“…Notably, these correlations were strongest for the insoluble vascular fraction and weakest for total brain homogenate (Extended Data Fig. 6 ), corroborating the association of increased MFG-E8 levels specifically with CAA in mice (as also indicated by a recent independent study 22 ). Although we could not confirm the presence of medin in our mouse samples biochemically (owing to the lack of a high affinity antibody for western blotting of mouse medin), these data demonstrate that the medin precursor protein MFG-E8 is highly enriched in the vasculature and is further increased with CAA, providing an explanation for why genetic medin deficiency may primarily affect vascular amyloid-β aggregation.…”

Section: Medin Promotes Vascular Amyloid-β Depositionsupporting

confidence: 86%

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Wagner

Degenhardt

Veit

et al. 2022

Nature

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Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age1,2, making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction3. Here we demonstrate in amyloid-β precursor protein (APP) transgenic mice and in patients with Alzheimer’s disease that medin co-localizes with vascular amyloid-β deposits, and that in mice, medin deficiency reduces vascular amyloid-β deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-β burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimer’s disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-β to promote its aggregation, as medin forms heterologous fibrils with amyloid-β, affects amyloid-β fibril structure, and cross-seeds amyloid-β aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-β deposition in the blood vessels of the brain.

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Section: Medin Promotes Vascular Amyloid-β Depositionsupporting

confidence: 86%

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Wagner

Degenhardt

Veit

et al. 2022

Nature

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“…It promotes Aβ aggregation by forming heterologous fibrils and thus is suggested as a therapeutic target for vascular damage prevention [44]. It is also observed to be highly associated with CAA pathology and has been proposed as a CSF biomarker [45]. Up-regulated in our disease-like mouse model was also Dedicator of Cytokinesis 9 (Dock9), a guanine nucleotide-exchange factor (Gef) that activates Cell Division Cycle 42 (Cdc42) [46].…”

Section: Discussionmentioning

confidence: 82%

Suspension TRAPping Filter (sTRAP) Sample Preparation for Quantitative Proteomics in the Low µg Input Range Using a Plasmid DNA Micro-Spin Column: Analysis of the Hippocampus from the 5xFAD Alzheimer’s Disease Mouse Model

Thanou

Koopmans

Pita-Illobre

et al. 2023

Cells

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Suspension TRAPping filter (sTRAP) is an attractive sample preparation method for proteomics studies. The sTRAP protocol uses 5% SDS that maximizes protein solubilization. Proteins are trapped on a borosilicate glass membrane filter, where SDS is subsequently removed from the filter. After trypsin digestion, peptides are analyzed directly by LC-MS. Here, we demonstrated the use of a low-cost plasmid DNA micro-spin column for the sTRAP sample preparation of a dilution series of a synapse-enriched sample with a range of 10–0.3 µg. With 120 ng tryptic peptides loaded onto the Evosep LC system coupled to TimsTof Pro 2 mass spectrometer, we identified 5700 protein groups with 4% coefficient of variation (CoV). Comparing other sample preparation protocols, such as the in-gel digestion and the commercial Protifi S-TRAP with the plasmid DNA micro-spin column, the last is superior in both protein and peptide identification numbers and CoV. We applied sTRAP for the analysis of the hippocampal proteome from the 5xFAD mouse model of Alzheimer’s disease and their wildtype littermates, and revealed 121 up- and 54 down-regulated proteins. Protein changes in the mutant mice point to the alteration of processes related to the immune system and Amyloid aggregation, which correlates well with the known major Alzheimer’s-disease-related pathology. Data are available via ProteomeXchange with the identifier PXD038443.

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“…The levels were significantly lower in patients with rheumatoid arthritis, 60 systemic sclerosis, 49 coronary atherosclerotic heart disease, 61 dilated cardiomyopathy, 52 and cerebral amyloid angiopathy. 62 The levels were significantly higher in patients with sepsis, 54 type 2 diabetes mellitus, 63 SLE, 64,65 and aneurysmal subarachnoid hemorrhage. 66 In patients with cancer, the serum levels of MFG-E8 were shown to be higher in patients with TNBC 67 but lower in patients with hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 91%

“…In various diseases other than cancer, the levels of systemic MFG‐E8 were measured and compared with those in healthy donors. The levels were significantly lower in patients with rheumatoid arthritis, 60 systemic sclerosis, 49 coronary atherosclerotic heart disease, 61 dilated cardiomyopathy, 52 and cerebral amyloid angiopathy 62 . The levels were significantly higher in patients with sepsis, 54 type 2 diabetes mellitus, 63 SLE, 64,65 and aneurysmal subarachnoid hemorrhage 66 .…”

Section: Discussionmentioning

confidence: 97%

Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG‐E8

Mizote,

Inoue,

Akazawa

et al. 2024

Cancer Science

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The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule‐epidermal growth factor‐factor 8 (MFG‐E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG‐E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor‐derived and systemically existing MFG‐E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL‐dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG‐E8, and that such responses were enhanced further with the administration of anti‐PD‐1 antibody. In mice with decreased levels of systemic MFG‐E8, the dominance of regulatory T cells in tumor‐infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG‐E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG‐E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG‐E8, but not MFG‐E8 expression in tumor cells, before the treatment was associated with objective responses to anti‐PD‐1 therapy in patients with non‐small cell lung cancer. These results suggest that systemic MFG‐E8 plays a critical role during the immunological initiation process of antigen‐presenting cells to increase tumor‐specific CTLs. Regulation of the systemic level of MFG‐E8 might induce efficient antitumor immune responses and enhance the potency of anti‐PD‐1 therapy.

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MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy

Cited by 12 publications

References 79 publications

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease

Suspension TRAPping Filter (sTRAP) Sample Preparation for Quantitative Proteomics in the Low µg Input Range Using a Plasmid DNA Micro-Spin Column: Analysis of the Hippocampus from the 5xFAD Alzheimer’s Disease Mouse Model

Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG‐E8

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