title: The sulfate moieties of glycosaminoglycans are critical for the enhancement of beta-amyloid protein fibril formation.
abstract: Our previous studies have demonstrated that perlecan and perlecan-derived glycosaminoglycans (GAGs) not only bind beta-amyloid protein (Abeta) 1-40 and 1-42, but are also potent enhancers of Abeta fibril formation and stabilize amyloid fibrils once formed. However, it was not determined which moieties in perlecan heparan sulfate GAG chains may be responsible for the observed effects and whether other GAGs were also capable of a similar enhancement of Abeta fibril formation as observed with perlecan GAGs. In the present study, thioflavin T fluorometry (over a 1-week period) was used to extend our previous studies and to test the hypothesis that the sulfate moiety is critical for the enhancing effects of heparin/heparan sulfate GAGs on Abeta 1-40 fibrillogenesis. This hypothesis was confirmed when removal of all sulfates from heparin (i.e., completely desulfated N-acetylated heparin) led to a complete loss in the enhancement of Abeta fibrillogenesis as demonstrated in both thioflavin T fluorometry and Congo red staining studies. On the other hand, removal of O-sulfate from heparin (i.e., completely desulfated N-sulfated heparin), and to a lesser extent N-sulfate (i.e., N-desulfated N-acetylated heparin), resulted in only a partial loss of the enhancement of Abeta 1-40 fibril formation. These studies indicate that the sulfate moieties of GAGs are critical for enhancement of Abeta amyloid fibril formation. In addition, other sulfated molecules such as chondroitin-4-sulfate, dermatan sulfate, dextran sulfate, and pentosan polysulfate all significantly enhanced (greater than twofold by 3 days) Abeta amyloid fibril formation. These latter findings indicate that deposition and accumulation of other GAGs at sites of Abeta amyloid deposition in Alzheimer's disease brain may also participate in the enhancement of Abeta amyloidosis.
authors: Department of Pathology, University of Washington, Seattle 98195-6480, USA.
authors: G M
authors: GM
authors: Castillo
authors: W
authors: W
authors: Lukito
authors: T N
authors: TN
authors: Wight
authors: A D
authors: AD
authors: Snow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004396:Coloring Agents; D003224:Congo Red; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism / Q000494:pharmacology; D013552:Swine
chemical_list: D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D005343:Fibrinolytic Agents; D006025:Glycosaminoglycans; D010446:Peptide Fragments; D013431:Sulfates; C078592:amyloid beta-protein (1-40); D003224:Congo Red; D006493:Heparin