Development of photocrosslinked sialic acid containing polymers for use in Abeta toxicity attenuation.
beta-Amyloid peptide (Abeta), the primary protein component in senile plaques associated with Alzheimer's disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Abeta-neuronal membrane interaction plays a crucial role in Abeta toxicity. More specifically, it is thought that Abeta interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have hypothesized that the Abeta-membrane sialic acid interaction could be inhibited through use of a biomimic multivalent sialic acid compound that would compete with the cell surface for Abeta binding. To explore this hypothesis, we synthesized a series of photocrosslinked sialic acid containing oligosaccharides and tested their ability to bind Abeta and attenuate Abeta toxicity in cell culture assays. We show that a polymer prepared via the photocrosslinking of disialyllacto-N-tetraose (DSLNT) was able to attenuate Abeta toxicity at low micromolar concentrations without adversely affecting the cell viability. Polymers prepared from mono-sialyl-oligosaccharides were less effective at Abeta toxicity attenuation. These results demonstrate the feasibility of using photocrosslinked sialyl-oligosaccharides for prevention of Abeta toxicity in vitro and may provide insight into the design of new materials for use in attenuation of Abeta toxicity associated with AD.
Chemical and Biochemical Engineering, University of Maryland, Baltimore County, UMBC 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Christopher B
CB
Cowan
Gerard L
GL
Coté
Theresa A
TA
Good
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000528:radiation effects; D015394:Molecular Structure; D019158:N-Acetylneuraminic Acid / Q000737:chemistry* / Q000528:radiation effects; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D009844:Oligosaccharides; D011108:Polymers; D019158:N-Acetylneuraminic Acid