Role of proteoglycans and glycosaminoglycans in the pathogenesis of Alzheimer's disease and related disorders: Amyloidogenesis and therapeutic strategies—A review

Abstract

The extracellular accumulation of amyloid beta proteins (Abetas) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). The binding of Abetas to extracellular membranes (ECMs) is a critical step in developing AD. Abetas bind to many biomolecules, including lipids, proteins, and proteoglycans (PGs). PGs play several roles in amyloid formation, including promoting the aggregation of Abetas into insoluble amyloid fibrils, which contributes to the increased neurotoxicity of Abetas. Although Abetas 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 Abetas are known to colocalize in senile plaques (SPs) and neurofibrillary tangles (NFTs) in the AD brain. The binding site of PGs to Abetas has been identified in the 13-16-amino-acid region (His-His-Gln-Lys) of Abetas 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 Abetas and enhance Abeta fibril formation. Low-molecular-weight heparins (LMWHs) can reverse the process of amyloidosis to inhibit fibril formation by blocking the formation of beta-plated structures, suggesting a possible therapeutic approach using LMWHs to interfere with the interaction between PGs and Abetas and to arrest or prevent amyloidogenesis.

In vivo molecular imaging of peripheral amyloidosis using heparin-binding peptides

“…Because of the critical role played by heparin in the coagulation cascade and the importance of heparin-like binding motifs expressed by signaltransducing cellular glycosaminoglycans, there has been considerable interest in identifying and characterizing heparin-binding peptides (34). In addition, several recent in vitro studies have shown that highly sulfated heparin catalyzes the fibrillogenesis of amyloid precursor proteins, including Ig light chains, β-2-microglobulin, Aβ, and sAA, relative to less-sulfated glycosaminoglycans (35)(36)(37). Based on our hypothesis that HS in amyloid is heparin-like, we synthesized a panel of heparinbinding peptides and assessed their ability to bind amyloid in vivo.…”

Pharmacology of Heparin and Related Drugs

“…Although the physiologic role of APP is not known, it has been suggested that the secreted ectodomain of APP acts as a growth factor and utilizes cell surface HS as a low-affinity coreceptor (Reinhard et al, 2013). The roles of GAGs and proteoglycans in Ab aggregation, and as potential antiamyloidogenesis agents, are the subject of an interesting review (Ariga et al, 2010), in which a number of potential therapeutic applications of GAGs are discussed.…”

Sugar glues for broken neurons

“…Less sulfated HS mediates uptake and degradation of AB in non-disease states; however, the highly sulfated HS inhibits this cellular uptake of AB. (93–95), and references therein) These deposits of highly sulfated HS can be substantially degraded by Sulf-1 and Sulf-2, suggesting the presence of 6- O -sulfates in significant amounts. (96) It has also been shown that the source of this highly sulfated HS is the nearby neuronal population and that HS is important for regulation of the Alzheimer’s β-secretase (BACE1).…”

“…Previous research also showed that HS, CS, and KS can all interact with AB peptides and enhance the shift of AB42 peptides to the β-sheet confirmation. (95) GAGs have been shown to be involved in aggregation and precipitation of amyloid fibrils, leading to increase in neurotoxicity. (98) Low molecular weight (LMW) heparin can compete with endogenous HS for binding to AB and inhibit the formation of fibrils.…”