Alzheimer's disease and heparan sulfate proteoglycan

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Cardinal histopathologic changes of AD are neurofibrillary tangles (NFTs) and deposits of beta-amyloid protein (A-beta) in the form of neuritic plaques (NPs). Several different mutations found in patients with familial AD have been demonstrated to increase A-beta production, resulting in a common pathological cascade of beta-amyloidosis in the brain. Heparan sulfate proteoglycan (HSPG) has been co-localized with both A-beta in the NPs and NFTs. The proteoglycans are a family of complex macromolecules consisting of a protein core to which glycosaminoglycan (GAG) chains are covalently attached. HSPG has been shown to bind to A-beta, accelerate its fibril formation, and maintain its fibril stability. In AD and other neurodegenerative disorders, tau becomes hyperphosphorylated hence it is unable to bind to microtubules which results in the production of paired helical filaments, a building unit of NFTs. It has been shown in vitro that sulfated GAGs induce the formation of paired helical-like filaments under physiological conditions from tau. Furthermore, an interaction between HSPG and apolipoprotein E (a potent risk factor of AD) has been shown to be involved in neurodegeneration. Thus, substantial evidence exists to underscore important roles of HSPG in the etiology of AD.