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Glypican‐1 as an Aβ binding HSPG in the human brain: Its localization in DIG domains and possible roles in the pathogenesis of Alzheimer's disease
Author(s) -
Watanabe Norifumi,
Araki Wataru,
Chui De-Hua,
Makifuchi Takao,
Ihara Yasuo,
Tabira Takeshi
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-1040fje
Subject(s) - microbiology and biotechnology , chemistry , senile plaques , heparan sulfate , amyloid (mycology) , amyloid precursor protein secretase , pathogenesis , perlecan , alzheimer's disease , cell , amyloid precursor protein , biochemistry , biology , disease , pathology , medicine , immunology , inorganic chemistry
ABSTRACT Previous studies have suggested that heparan sulfate proteoglycans (HSPGs) play a role in deposition of β‐amyloid protein (Aβ) in the Alzheimer's disease (AD) brain. In the present study, we demonstrated that glypican‐1 can bind fibrillar Aβ, 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 Aβ production exist and Aβ 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 Aβ toxicity. The results raise the possibility that glypican‐1 interacts with oligomerized or polymerized Aβ 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 Aβ.