Abstract
The extracellular accumulation of amyloid β proteins (Aβs) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). The binding of Aβs to extracellular membranes (ECMs) is a critical step in developing AD. Aβs bind to many biomolecules, including lipids, proteins, and proteoglycans (PGs). PGs play several roles in amyloid formation, including promoting the aggregation of Aβs into insoluble amyloid fibrils, which contributes to the increased neurotoxicity of Aβs. Although Aβs readily self‐aggregate to form amyloid fibrils in vitro, their binding to PGs and heparin enhances amyloid aggregation and fibril formation. The sulfate moiety in glycosaminoglycans (GAGs), the carbohydrate portion of PGs, is necessary for the formation of amyloid fibrils; no fibrils are observed in the presence of hyaluronic acid (HA), a nonsulfated GAG. PGs and Aβs are known to colocalize in senile plaques (SPs) and neurofibrillary tangles (NFTs) in the AD brain. The binding site of PGs to Aβs has been identified in the 13–16‐amino‐acid region (His‐His‐Gln‐Lys) of Aβs and represents a unique target site for inhibition of amyloid fibril formation; His13 in particular is an important residue critical for interaction with GAGs. The sulfate moieties of GAGs play a critical role in the binding to Aβs and enhance Aβ fibril formation. Low‐molecular‐weight heparins (LMWHs) can reverse the process of amyloidosis to inhibit fibril formation by blocking the formation of β‐plated structures, suggesting a possible therapeutic approach using LMWHs to interfere with the interaction between PGs and Aβs and to arrest or prevent amyloidogenesis. © 2010 Wiley‐Liss, Inc.