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Matrix pathobiology
Heparan Sulfate Subdomains that are Degraded by Sulf Accumulate in Cerebral Amyloid ß Plaques of Alzheimer's Disease: Evidence from Mouse Models and Patients

https://doi.org/10.1016/j.ajpath.2012.01.015Get rights and content

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.

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This work was supported by grants from the Japanese Health and Labour Sciences Research (Comprehensive Research on Aging and Health H19-001 and H22-007 to K.U., H20-007 to M.M.), Grants-in-Aid from the Ministry of Education, Science, Sports and Culture (22790303 to K.U. and JBBNNR, Comprehensive Brain Science Network to H.A.), and in part from the Sanofi-Aventis Science Foundation of Japan (to K.U.), the Naito Science Foundation (to K.U.), the Takeda Science Foundation (to K.U.), and the Daiko Foundation (to K.U.).

Present address of M.B., F. Hoffmann-La Roche Ltd, pRED, CNS Discovery, CH-4070, Basel, Switzerland.

Supplemental material for this article can be found on http://ajp.amjpathol.org or at doi: 10.1016/j.ajpath.2012.01.015.

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