Study Of The Interaction Between Heparin Oligosaccharides And β-amyloid Peptide Using NMR

Alzheimer’s disease(AD)is a neurodegenerative disease that mainly occurs in the elderly people.With the intensified aging trend of population,AD has gradually become the most common disease seriouslyaffecting the health ofelder people.β-amyloid peptide and protein tau are the major components of amyloid plaques and neurofibrillary tangles,respectively,which are the pathological diagnostic criteria of AD.However,neurofibrillary tangles can be observed in multiple neurodegenerative diseases and Aβ becomes the main substance to study AD.Aβ is the metabolite in the normal physiological process,while the disordered pathological change of Aβ results in AD.Glycosaminoglycan(GAG)can either promote or inhibit the aggregation of Aβ.Sulfated GAG can effectively accelerate the fibrosis aggregation of Aβ and stabilize the senile plaques.However,the unsulfated hyaluronic acid(HA)cannot promote the fibrosis aggregate of Aβ.Heparin oligosaccharides can bind to Aβ competitively resulting in effective inhibition of Aβ fibrosis aggregation and neurotoxicity decrease.Heparin oligosaccharides can effectively across the blood brain barrier(BBB)and directly bind to Aβ.Heparin oligosaccharides C3 mixture,a kind of low molecular weight heparin(LMWH)derivatives,have been used in treatment as inhibitors of Aβaggregation.These drugs are mixtures.Because these mixtures can interact with many different kinds of proteins and play different physiological activities,they may have potential side effects.Therefore,study of the interaction between Aβ and heparin oligosaccharides in the mean of structure-activity relationship is still important.This project is to study the interaction between oligosaccharides and Aβ40.Three kinds of heparin tetrasaccharides dp4-1,dp4-3,dp4-4 were prepared and their structures and one hexasaccahride(Fondaparinux sodium)were characterized by nuclear magnetic resonance(NMR)and mass spectrum(MS)as ΔUA2S(1→4)GlcNS6S(1→4)IdoA2S(1→4)GlcNS, ΔUA2S(1→4)GlcNS6S(1→4)GlcA(1→4)GlcNS6S,ΔUA2S(1→4)GlcNS6S(1→4)IdoA2S(1→4)GlcNS6S,and GlcNS6S(1→4)GlcA(1→4)GlcNS3S6S(1→4)IdoA2S(1→4)GlcNS6SOMe,respectively.Gel mobility shift assay(GMSA)and nuclear magnetic resonance(NMR)were used to study the interaction between heparin oligosaccharides and Aβ40.Experimental result demonstrates that the order of binding ability between heparin tetrasaccharides and Aβ40 isdp4-4>dp4-1>dp4-3.IdoA2S is the essential binding monosaccarhide,while the 6S of GlcNS6S could enhance the interaction.The 3S of fondaparinux sodium withspecific anti-coagulant activity was not involved in the binding between fondaparinux sodium and Aβ40.