Identification of molecular compounds critical to Alzheimer's‐like plaque formation

Abstract

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.

Genome-wide analysis ofSaccharomyces cerevisiaeidentifies cellular processes affecting intracellular aggregation of Alzheimer's amyloid-β42: importance of lipid homeostasis

“…In human brain, myo -inositol is the most abundant stereoisomer (Haris et al ., 2011) and forms small stable micelles with the Aβ peptide (McLaurin et al ., 1998). Amyloid fibril formation is inhibited by myo -inositol (Gellermann et al ., 2007), and complexation of Aβ with inositol protects neuronal cultures from Aβ toxicity (McLaurin et al ., 2000). Similarly, the scyllo -inositol stereoisomer inhibits amyloid formation (Li et al ., 2012; Ma et al ., 2012), and treatment of animal AD models with scyllo -inositol reduces plaque formation and improves memory performance and hippocampal synaptic plasticity (McLaurin et al ., 2006; Aytan et al ., 2013).…”

Interactions between dendrimers and heparin and their implications for the anti-prion activity of dendrimers

“…Heparin has been found to induce aggregation and b-sheet formation. 10,11 Sulfated GAGs have frequently been identified as potential physiological ligands of PrP C , creating oligomeric complexes with PrP. 12 However, there are contradictory hypotheses about the role of GAGs in the infection, since both enhancing and inhibiting effects have been identified.…”