title: Glypican-1 as an Abeta binding HSPG in the human brain: its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease.
abstract: Previous studies have suggested that heparan sulfate proteoglycans (HSPGs) play a role in deposition of beta-amyloid protein (Abeta) in the Alzheimer's disease (AD) brain. In the present study, we demonstrated that glypican-1 can bind fibrillar Abeta, and the binding is mainly mediated by heparan sulfate (HS) chains. Further analysis revealed that glypican-1 is the major HSPG localized in detergent-insoluble glycosphingolipid-enriched (DIG) domains where all machineries for Abeta production exist and Abeta is accumulated as monomeric and oligomeric forms. Immunohistochemical studies demonstrated that glypican-1 is localized in primitive plaques as well as classic plaques. Moreover, overexpression of glypican-1 and amyloid precursor protein in SH-SY5Y cells resulted in reduced cell viability and made cells more susceptible to thapsigargin-induced stress and Abeta toxicity. The results raise the possibility that glypican-1 interacts with oligomerized or polymerized Abeta in such a specific compartment as DIG, resulting not only in amyloid deposition in senile plaques of AD brain, but also in accelerating neuronal cell death in response to stress and Abeta.
authors.affiliation: National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. watanabn@nils.go.jp
authors.forename: Norifumi
authors.initials: N
authors.lastname: Watanabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Araki
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Chui
authors.forename: Takao
authors.initials: T
authors.lastname: Makifuchi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003902:Detergents / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D005260:Female; D006028:Glycosphingolipids / Q000032:analysis* / Q000737:chemistry*; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008297:Male; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012995:Solubility / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003902:Detergents; D006028:Glycosphingolipids; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D019284:Thapsigargin