title: Non-toxic amyloid beta formed in the presence of glypican-1 or its deaminatively generated heparan sulfate degradation products.
abstract: The amyloid beta (Aβ) peptides (mainly Aβ40 and Aβ42), which are derived from the amyloid precursor protein (APP), can oligomerize into antibody A11-positive, neurotoxic species, believed to be involved in Alzheimer's disease. Interestingly, APP binds strongly to the heparan sulfate (HS) proteoglycan (PG) glypican-1 (Gpc-1) in vitro and both proteins are colocalized inside cells. In endosomes, APP is proteolytically processed to yield Aβ peptides. The HS chains of S-nitrosylated (SNO) Gpc-1 PG are cleaved into anhydromannose (anMan)-containing di- and oligosaccharides by an NO-dependent reaction in the same compartments. Here, we have studied the toxicity of oligomers/aggregates of Aβ40 and Aβ42, as well as Aβ40/42 mixtures that were formed in the presence of immobilized Gpc-1 PG or immobilized HS oligosaccharides. Afterwards, Aβ was displaced from the matrices, analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for A11 immunoreactivity, for effects on growth of mouse N2a neuroblastoma cells and for membrane leakage in rat cortical neurons. HS generally promoted and accelerated Aβ multimerization into oligomers as well as larger aggregates that were mostly A11 positive and showed toxic effects. However, non-toxic Aβ was formed in the presence of Gpc-1 PG or when anMan-containing HS degradation products were simultaneously generated. Both toxic and non-toxic Aβ peptides were taken up by the cells but toxic forms appeared to enter the nuclei to a larger extent. The protection afforded by the presence of HS degradation products may reflect a normal intracellular function for the Aβ peptides.
authors.affiliation: Department of Experimental Medical Science, Division of Neuroscience, Glycobiology Group.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.forename: Karsten
authors.initials: K
authors.lastname: Ruscher
authors.forename: Lars-Åke
authors.initials: LÅ
authors.lastname: Fransson
authors.forename: Katrin
authors.initials: K
authors.lastname: Mani
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D003641:Deamination; D053673:Glypicans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D053673:Glypicans; D006497:Heparan Sulfate
keywords: amyloid beta; glypican-1; heparan sulfate; oligomerization; toxicity