Identification of molecular compounds critical to Alzheimer's-like plaque formation.
Amyloid diseases are characterized by the formation of insoluble amyloid fibrils from previously soluble polypeptides. In Alzheimer's disease (AD), amyloid fibrils, formed from beta-amyloid peptides, are deposited as extracellular amyloid plaques only inside the brain. As previously shown, Alzheimer's-like plaque formation in human monocyte culture recapitulates the features of in vivo amyloid plaque formation. Here we show that this cell model can be used to screen compounds that potentially influence amyloid formation in a throughput manner. We found that cellular amyloid fibril formation can be enhanced by dextran sulfate as well as heparin and can be impaired by stabilization of a micell-like beta-amyloid conformer by using myoinositol or by inhibition of phagocytosis with cytochalasin D. Altogether, our data demonstrate the utility of this cell model for investigating pathways and molecular interactions critical to amyloidogenesis.
Gellermann
Gerald P
GP
Leibniz Institute for Age Research, Fritz-Lipmann Institut, Jena, Germany. gellermann@biocone.com
Ullrich
Kathrin
K
Unger
Christiane
C
Fändrich
Marcus
M
Sauter
Simon
S
Diekmann
Stephan
S
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002478:Cells, Cultured; D002807:Chondroitin / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007294:Inositol / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008854:Microscopy, Electron; D009000:Monocytes / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D011339:Probenecid / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D015638:Cytochalasin D; D007294:Inositol; D006493:Heparin; D002807:Chondroitin; D016264:Dextran Sulfate; D019833:Genistein; D011339:Probenecid; D015739:Nocodazole