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.
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.
Watanabe
Norifumi
N
National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. watanabn@nils.go.jp
Araki
Wataru
W
Chui
De-Hua
DH
Makifuchi
Takao
T
Ihara
Yasuo
Y
Tabira
Takeshi
T
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003902:Detergents; D006028:Glycosphingolipids; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D019284:Thapsigargin