title: Heparan sulfate subdomains that are degraded by Sulf accumulate in cerebral amyloid ß plaques of Alzheimer's disease: evidence from mouse models and patients.
abstract: Alzheimer's disease (AD) is characterized by extracellular cerebral accumulation of amyloid β peptide (Aβ). Heparan sulfate (HS) is a glycosaminoglycan that is abundant in the extracellular space. The state of sulfation within the HS chain influences its ability to interact with a variety of proteins. Highly sulfated domains within HS are crucial for Aβ aggregation in vitro. Here, we investigated the expression of the sulfated domains and HS disaccharide composition in the brains of Tg2576, J20, and T41 transgenic AD mouse models, and patients with AD. RB4CD12, a phage display antibody, recognizes highly sulfated domains of HS. The RB4CD12 epitope is abundant in the basement membrane of brain vessels under physiological conditions. In the cortex and hippocampus of the mice and patients with AD, RB4CD12 strongly stained both diffuse and neuritic amyloid plaques. Interestingly, RB4CD12 also stained the intracellular granules of certain hippocampal neurons in AD brains. Disaccharide compositions in vessel-enriched and nonvasculature fractions of Tg2576 mice and AD patients were found to be comparable to those of non-transgenic and non-demented controls, respectively. The RB4CD12 epitope in amyloid plaques was substantially degraded ex vivo by Sulf-1 and Sulf-2, extracellular HS endosulfatases. These results indicate that formation of highly sulfated HS domains may be upregulated in conjunction with AD pathogenesis, and that these domains can be enzymatically remodeled in AD brains.
authors.affiliation: Section of Pathophysiology and Neurobiology, National Center for Geriatrics and Gerontology, Obu, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hosono-Fukao
authors.forename: Shiori
authors.initials: S
authors.lastname: Ohtake-Niimi
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hoshino
authors.forename: Markus
authors.initials: M
authors.lastname: Britschgi
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Md Motarab
authors.initials: MM
authors.lastname: Hossain
authors.forename: Kazuchika
authors.initials: K
authors.lastname: Nishitsuji
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchimura
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004187:Disaccharides / Q000378:metabolism; D004195:Disease Models, Animal; D019317:Evidence-Based Medicine / Q000379:methods; D005260:Female; D006497:Heparan Sulfate / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008970:Molecular Weight; D058225:Plaque, Amyloid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013429:Sulfatases / Q000494:pharmacology; D015238:Sulfotransferases / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D004187:Disaccharides; D006497:Heparan Sulfate; D011994:Recombinant Proteins; D013429:Sulfatases; D015238:Sulfotransferases; C486773:Sulf1 protein, mouse; C514911:Sulf2 protein, mouse