Pathology Of Amyloidosis Research Articles

Amyloid fibril cytotoxicity and associated disorders.

Misfolded proteins assemble into fibril structures that are called amyloids. Unlike usually folded proteins, misfolded fibrils are insoluble and deposit extracellularly or intracellularly. Misfolded proteins interrupt the function and structure of cells and cause amyloid disease. There is increasing evidence that the most pernicious species are oligomers. Misfolded proteins disrupt cell function and cause cytotoxicity by calcium imbalance, mitochondrial dysfunction, and intracellular reactive oxygen species. Despite profound impacts on health, social, and economic factors, amyloid diseases remain untreatable. To develop new therapeutics and to understand the pathological manifestations of amyloidosis, research into the origin and pathology of amyloidosis is urgently needed. This chapter describes the basic concept of amyloid disease and the function of atypical amyloid deposits in them.

Contribution of Sulfated Glycosaminoglycans to the Pathology of Amyloidosis

Contribution of Sulfated Glycosaminoglycans to the Pathology of Amyloidosis

Contribution of Sulfated Glycosaminoglycans to the Pathology of Amyloidosis

Contribution of Sulfated Glycosaminoglycans to the Pathology of Amyloidosis

Comprehensive proteomic profiles of mouse AApoAII amyloid fibrils provide insights into the involvement of lipoproteins in the pathology of amyloidosis

Amyloidosis is a disorder characterized by extracellular fibrillar deposits of misfolded proteins. The amyloid deposits commonly contain several non-fibrillar proteins as amyloid-associated proteins, but their roles in amyloidosis pathology are still unknown. In mouse senile amyloidosis, apolipoprotein A-II (ApoA-II) forms extracellular amyloid fibril (AApoAII) deposits with other proteins (AApoAII-associated proteins) in many organs. We previously reported that R1.P1-Apoa2c mice provide a reproducible model of AApoAII amyloidosis. In order to investigate the sequential alterations of AApoAII-associated protein, we performed a proteomic analysis of amyloid fibrils extracted from mouse liver tissues that contained different levels of AApoAII deposition. We identified 6 AApoAII-associated proteins that constituted 20 of the top-ranked proteins in mice with severe AApoAII deposition. Although the amount of AApoAII-associated proteins increased with the progression of amyloidosis, the relative abundance of AApoAII-associated proteins changed little throughout the progression of amyloidosis. On the other hand, plasma levels of these proteins showed dramatic changes during the progression of amyloidosis. In addition, we confirmed that AApoAII-associated proteins were significantly associated with lipid metabolism based on functional enrichment analysis, and lipids were co-deposited with AApoAII fibrils from early stages of development of amyloidosis. Thus, these results demonstrate that lipoproteins are involved in AApoAII amyloidosis pathology. SignificanceThis study presented proteomic profiles of AApoAII amyloidosis during disease progression and it revealed co-deposition of lipids with AApoAII deposits based on functional analyses. The relative abundance of AApoAII-associated proteins in the amyloid fibril fractions did not change over the course of development of AApoAII amyloidosis pathology. However, their concentrations in plasma changed dramatically with progression of the disease. Interestingly, several AApoAII-associated proteins have been found as constituents of lipid-rich lesions of other degenerative diseases, such as atherosclerosis and age-related macular degeneration. The common protein components among these diseases with lipid-rich deposits could be accounted for by a lipoprotein retention model.

Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils

Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serine with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. We anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development of structure-specific imaging agents and aggregation inhibitors.

Enzymatic remodeling of heparan sulfate: a therapeutic strategy for systemic and localized amyloidoses?

In 1854, Rudolf Virchow introduced the term “amyloid” to indicate white waxy deposits that stained positive for iodine and that were found in many organs of patients with chronic inflammatory diseases. He observed that these deposits stained pale blue after treatment with iodine and became dark blue or black after subsequent addition of sulfuric acid, in a similar manner to that of cellulose or carbohydrate. He concluded that these deposits were carbohydrate in nature and termed the substances “;amyloid,” a name that was derived from the Latin amylum and the Greek amylon, meaning starch (Virchow, 1854). However, in 1859, Friedrich and Kekule used protein-staining dyes and showed that these deposits were in fact protein in nature (Friedrich and Kekule, 1859). The term “amyloidosis” today refers to diseases in which amyloidogenic proteins deposit as insoluble fibrils in many tissues and organs, consistent with the conclusion of Friedrich and Kekule. These protein fibrils are characterized by having a β-structure, resistance to proteolysis, and specific binding to histochemical dyes such as Congo red and thioflavin that are used to identify amyloid deposits in tissues. Thus far, many in vivo observations revealed that amyloid deposits contain, besides protein fibrils, carbohydrate and other protein components derived from intra- and extracellular spaces. These non-amyloid components may be involved in the pathogenesis and pathology of amyloidosis, such as amyloid formation and amyloid-induced tissue damage. In the 1980s, Snow and Kisilevsky found that glycosaminoglycans (GAGs) were associated with tissue amyloid deposits (Snow and Kisilevsky, 1985). They identified the GAG as heparan sulfate (HS), which is a component of heparan sulfate proteoglycan (HSPG) and a member of the GAG family. HS is now known to be associated with different types of amyloid in systemic and localized amyloidoses. From this perspective, we will discuss here the possible roles of HS and its highly sulfated domains in the pathogenesis and pathology of amyloidosis.

Supramolecular Inhibition of Amyloid Fibrillation by Cucurbit[7]uril

AbstractAmyloid fibrils are insoluble protein aggregates comprised of highly ordered β‐sheet structures and they are involved in the pathology of amyloidoses, such as Alzheimer’s disease. A supramolecular strategy is presented for inhibiting amyloid fibrillation by using cucurbit[7]uril (CB[7]). CB[7] prevents the fibrillation of insulin and β‐amyloid by capturing phenylalanine (Phe) residues, which are crucial to the hydrophobic interactions formed during amyloid fibrillation. These results suggest that the Phe‐specific binding of CB[7] can modulate the intermolecular interaction of amyloid proteins and prevent the transition from monomeric to multimeric states. CB[7] thus has potential for the development of a therapeutic strategy for amyloidosis.

Supramolecular inhibition of amyloid fibrillation by cucurbit[7]uril.

Amyloid fibrils are insoluble protein aggregates comprised of highly ordered β-sheet structures and they are involved in the pathology of amyloidoses, such as Alzheimer's disease. A supramolecular strategy is presented for inhibiting amyloid fibrillation by using cucurbit[7]uril (CB[7]). CB[7] prevents the fibrillation of insulin and β-amyloid by capturing phenylalanine (Phe) residues, which are crucial to the hydrophobic interactions formed during amyloid fibrillation. These results suggest that the Phe-specific binding of CB[7] can modulate the intermolecular interaction of amyloid proteins and prevent the transition from monomeric to multimeric states. CB[7] thus has potential for the development of a therapeutic strategy for amyloidosis.

A Putative Role for Cathepsin K in Degradation of AA and AL Amyloidosis

The aims of this study were to investigate the role of cathepsin K in the pathology of amyloidosis by demonstrating its presence in multinucleated giant cells (MGCs) adjacent to amyloid deposits, and determining its ability to degrade amyloid fibril proteins in vitro. The study was performed using autopsy and biopsy specimens from patients with AA or AL amyloidosis. In six (55%) patients with AA amyloidosis and seven (58%) patients with AL amyloidosis, variable numbers of CD68-immunoreactive MGCs were found adjacent to amyloid deposits. In each case strong cytoplasmic immunostaining for cathepsin K was found in MGCs; immunostaining of amyloid deposits was present in five (45%) patients with AA amyloidosis and three (25%) patients with AL amyloidosis. In vitro degradation experiments showed that recombinant cathepsin K completely degraded AA amyloid fibril proteins at pH 5.5 as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Less effective degradation took place at pH 7.4 and there was no degradation in the presence of a general cysteine protease inhibitor (E64) or in the absence of cathepsin K. This is the first study to show that cathepsin K is expressed in MGCs adjacent to amyloid deposits and to demonstrate its ability to degrade amyloid fibril proteins.

4) PATHOLOGY OF AMYLOIDOSIS

4) PATHOLOGY OF AMYLOIDOSIS

GEOGRAPHICAL PATHOLOGY OF AMYLOIDOSIS IN SINGAPORE.

GEOGRAPHICAL PATHOLOGY OF AMYLOIDOSIS IN SINGAPORE.

A modified technique for gingival biopsy in the diagnosis of secondary amyloidosis

The pathology of amyloidosis is presented together with the previous methods used in the diagnosis of this ailment. A modified procedure for securing a gingival biopsy is described.