Abstract
Amyloid is a complex pathologic matrix comprised principally of paracrystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloid diseases are rare, thus, routine diagnosis is often challenging. The glycosaminoglycans ubiquitously present in amyloid deposits are biochemically and electrochemically distinct from those found in the healthy tissues due to the high degree of sulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14, as novel agents for specifically targeting and imaging amyloid. Herein, we demonstrate that radiolabeled p5+14 effectively bound murine AA amyloid in vivo by using molecular imaging. Biotinylated peptide also reacted with the major forms of human amyloid in tissue sections as evidenced immunohistochemically. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients.
Highlights
Amyloidosis is a protein-folding disorder characterized by the aggregation and deposition of proteinaceous fibrils, associated with proteoglycans and serum-derived proteins, in vital organs and tissues [1,2,3]
Given that heparan sulfate (HS) is invariably associated with amyloid and has a distinct hypersulfation pattern, akin to that of heparin, we have explored the use of synthetic heparin-binding peptides as specific amyloid-targeting agents for the purpose of generating novel molecular imaging agents for the detection of disease in patients
The 45-amino acid sequence of peptide p5+14 (Table 1) contains 12 lysine residues and a tyrosine residue at position 4, which is a site for facile radioiodination of the peptide, to allow for single photon emission computed tomography (SPECT) and positron emission tomography (PET) molecular imaging studies
Summary
Amyloidosis is a protein-folding disorder characterized by the aggregation and deposition of proteinaceous fibrils, associated with proteoglycans and serum-derived proteins, in vital organs and tissues [1,2,3]. The deposits can be cerebral, as in patients with Alzheimer’s, Huntington’s or prion diseases, or involve visceral organs as seen in patients with light chain (AL) and inflammation-associated (AA) amyloidoses [4,5]. The systemic amyloidoses are orphan disorders but account for ~3500 new patients annually in the US alone [6]. More than 28 proteins have been identified as constituents of fibrils in amyloid deposits. It is the nature of these proteins that differentiate the diseases, define the treatment regimen, and establish the prognosis
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