Pathological amyloid fibrils and deposits and associated high charge-density heparan sulfate glycosaminoglycans

Pathological amyloid fibrils and deposits are the defining feature of amyloidosis, a group of diseases characterized by the extracellular accumulation of misfolded proteins (Merlini & Bellotti, 2003). These deposits are complex structures that, in addition to the protein fibrils themselves, ubiquitously contain accessory molecules such as high charge-density heparan sulfate glycosaminoglycans (HS GAGs) (Hancock et al., 2025). These hypersulfated GAGs play a critical role in the pathogenesis of the disease by promoting the misfolding of precursor proteins, facilitating fibril assembly, and stabilizing the resulting deposits against proteolytic degradation (Rumjon et al., 2012). Because these specific GAGs are a universal component of all amyloid types (e.g., AL, ATTR, AA, and Aβ) and are distinct from the GAGs found in healthy tissues, they serve as a pan-amyloid target for both therapy and diagnosis (Wall et al., 2017). Therapeutic approaches include GAG mimetics like eprodisate, which disrupt the fibril-GAG interaction, and fusion proteins like AT-02 and AT-03, which opsonize the deposits to induce clearance by the innate immune system (Selvarajah, 2021). Diagnostic agents such as evuzamitide (124I-p5+14) leverage the high affinity of polybasic peptides for these charged GAGs to enable sensitive PET imaging of amyloid deposits throughout the body (Hancock et al., 2025).

Other names

Amyloid-associated heparan sulfate glycosaminoglycansHypersulfated heparan sulfateAmyloid-associated GAGsPan-amyloid targetAmyloid-associated heparan sulfate proteoglycans (HSPGs)

Competitive inhibition of glycosaminoglycan-amyloid interaction; Opsonization of amyloid deposits for macrophage-mediated phagocytosis; Selective binding for diagnostic imaging.