Amyloid-glycosaminoglycan complex

The amyloid-glycosaminoglycan complex consists of insoluble protein fibrils and co-localized hypersulfated polysaccharides, primarily heparan sulfate, which are found in nearly all forms of amyloid deposits [1, 5]. These glycosaminoglycans (GAGs) act as pathological scaffolds that promote the transition of soluble proteins into beta-sheet-rich fibrils and stabilize them against proteolytic degradation [2, 7]. The interaction is largely mediated by electrostatic forces between the negatively charged sulfate groups of the GAGs and positively charged amino acid residues on the amyloidogenic proteins [7, 15]. This complex is a key driver in the pathogenesis of diseases such as Alzheimer's disease, where it facilitates amyloid-beta aggregation, and systemic amyloidoses like AL and AA amyloidosis [2, 9]. Therapeutic interventions, such as the GAG mimetic tramiprosate and its prodrug valiltramiprosate, aim to competitively inhibit this interaction to prevent fibril formation and enhance clearance [3, 6, 11]. However, targeting this complex presents challenges, including the potential for some mimetics to inadvertently promote tau protein aggregation or interfere with the physiological functions of endogenous GAGs [10].

Other names

Amyloid fibrils and associated hypersulfated glycosaminoglycans on fibril surfacesAmyloid-HSPG complexAmyloid-heparan sulfate complexGAG-amyloid interaction siteAmyloid-proteoglycan complex

Competitive inhibition of glycosaminoglycan binding to amyloidogenic proteins, which prevents the nucleation, elongation, and stabilization of amyloid fibrils [3, 4, 7].