The role of heparan sulfate in the generation of Abeta.

Alzheimer's disease is a fatal neurodegenerative disorder for which there are currently few treatments and no cure. Heparan sulfate, a heterogeneously sulfated glycosaminoglycan, has been identified as the first naturally occurring inhibitor of beta secretase, the rate-limiting step in the formation of Abeta, the peptide core of the amyloid plaques that cause Alzheimer's disease. Though heparan sulfate has frequently been implicated in the formation of fibrils, only fairly recently has its role as an inhibitor of beta secretase been recognized. This inhibitory activity is dependent on the structure and size of the heparan sulfate chain, with emphasis placed on the position of the sulfates. Heparan sulfate directly binds to beta secretase and causes a closed configuration of the catalytic site. Regulation of amyloid precursor protein (APP) beta secretase cleavage could occur at a number of cellular locations, including the Golgi complex, endosomal system and cell surface. Heparan sulfate also binds to APP and may sequester it away from beta secretase. These findings have led to the examination of heparan sulfate analogues, such as beta-secretase inhibitors, as a potential therapeutic approach to treat Alzheimer's disease.