Researchers Pinpoint Structure Within Proteoglycans Critical to Fibril Formation

Researchers at ProteoTech Inc. (Redmond, WA) and the University of Washington (Seattle) have pinpointed a structure within proteoglycans that enhances the formation of beta-amyloid protein fibrils or brain plaque deposits characteristic of Alzheimer's disease. In the April issue of the Journal of Neurochemistry, Gerardo Castillo, Director of Biochemistry at ProteoTech, and his colleagues report that the sulfate moieties of glycosaminoglycans (GAGs) are required for their observed enhancement of fibril formation.

Amyloid plaques and cerebrovascular amyloid deposits, found in all patients with Alzheimer's disease, contain a small 39–43 amino acid peptide, termed the beta-amyloid protein or Aß. Also accompanying this debilitating disease, which affects some 4–5 million Americans, is the accumulation of abnormal filaments (tangles) within neurons. Prior work from these researchers had established that perlecan and perlecan-derived GAGs not only bind Aß amyloid protein, but also enhance and stabilize fibril formation. However, it was not known what portion of the molecule is responsible for these effects, and whether other proteoglycans would behave similarly. In this report, experiments show that sulfate moieties are critical to the enhancement of fibril formation, as the complete removal of sulfates caused the GAGs to lose the ability to enhance fibrillogensis. In addition, other sulfated molecules (chondroitin-4-sulfate, dermatan sulfate, dextran sulfate, and pentosan polysulfate) were found to enhance fibril formation, further demonstrating the importance of sulfates in this process.

"To the extent that researchers better understand the formation, deposition, and persistence of ß-amyloid protein and amyloid fibrils, the better able we will be at identifying and engineering therapeutics to disrupt these deposits and address some of the pathology underlying Alzheimer's disease. New studies by our group reconfirm the importance of proteoglycans in the pathogenesis of Alzheimer's and suggest new approaches for the ultimate treatment of this disease," said Alan Snow, Research Associate Professor of Pathology at the University of Washington and one of the co-founders of ProteoTech Inc.

ProteoTech is a drug-discovery company that focuses on therapeutics and diagnostics for human disease utilizing proteoglycan technologies. In a related development, ProteoTech has been awarded two Small Business Innovative Research (SBIR) grants from the National Institutes of Health. A Phase I award of $227,501 was given for the isolation and identification of active amyloid inhibitory substances in its proprietary plant derivative, PTI-00703, an inhibitor fibril formation and growth. In addition, a $143,986 SBIR Phase I grant was awarded to investigate the structure of proteoglycans involved in plaque and fibril formation in Alzheimer's patients.

For more information, contact ProteoTech Inc., 14718 NE 87th Street, Redmond, WA 98052.

By Laura DeFrancesco