Wild type transthyretin-derived amyloid (ATTRwt) is the major component of non-hereditary transthyretin amyloidosis. Its accumulation in the heart of elderly patients is life threatening. A variety of genetic variants of transthyretin can lead to hereditary transthyretin amyloidosis, which shows different clinical symptoms, like age of onset and pattern of organ involvement. However, in the case of non-hereditary transthyretin amyloidosis ATTRwt fibril deposits are located primarily in heart tissue. In this structural study we analyzed ATTRwt amyloid fibrils from the heart of a patient with non-hereditary transthyretin amyloidosis. We present a 2.78 Å reconstructed density map of these ATTRwt fibrils using cryo electron microscopy and compare it with previously published V30M variants of ATTR fibrils extracted from heart and eye of different patients. All structures show a remarkably similar spearhead like shape in their cross section, formed by the same N- and C-terminal fragments of transthyretin with some minor differences. This demonstrates common features for ATTR fibrils despite differences in mutations and patients.

Purpose Amyloidosis is a disease group caused by pathological aggregation and deposition of peptides in diverse tissue sites. Recently, matrix‐assisted laser desorption/ionization mass spectrometry imaging coupled with ion mobility separation (MALDI‐IMS MSI) was introduced as a novel tool to identify and classify amyloidosis using single sections from formalin‐fixed and paraffin‐embedded cardiac biopsies. Here, we tested the hypothesis that MALDI‐IMS MSI can be applied to lung and gastrointestinal specimens. Experimental Design Forty six lung and 65 gastrointestinal biopsy and resection specimens with different types of amyloid were subjected to MALDI‐IMS MSI. Ninety three specimens included tissue areas without amyloid as internal negative controls. Nine cases without amyloid served as additional negative controls. Results Utilizing a peptide filter method and 21 known amyloid specific tryptic peptides we confirmed the applicability of a universal peptide signature with a sensitivity of 100% and a specificity of 100% for the detection of amyloid deposits in the lung and gastrointestinal tract. Additionally, the frequencies of individual m/z‐values of the 21 tryptic marker peptides showed organ‐ and tissue‐type specific differences. Conclusions and Clinical Relevance MALDI‐IMS MSI adds a valuable analytical approach to diagnose and classify amyloid and the detection frequency of individual tryptic peptides is organ‐/tissue‐type specific.

Amyloidosis is a disease caused by pathological fibril aggregation and deposition of proteins in different tissues and organs. Thirty-six fibril-forming proteins have been identified. So far, proteomic evaluation of amyloid focused on the detection and characterization of fibril proteins mainly for diagnostic purposes or to find novel fibril-forming proteins. However, amyloid deposits are a complex mixture of constituents that show organ-, tissue-, and amyloid-type specific patterns, that is the amyloid proteome. We carried out a comprehensive literature review on publications investigating amyloid via liquid chromatography coupled to tandem mass spectrometry, including but not limited to sample preparation by laser microdissection. Our review confirms the complexity and dynamics of the amyloid proteome, which can be divided into four functional categories: amyloid proteome-category 1 (APC1) includes exclusively fibrillary proteins found in the patient; APC2 includes potential fibril-forming proteins found in other types of amyloid; and APC3 and APC4 summarizes non-fibril proteins-some being amyloid signature proteins. Our categorization may help to systemically explore the nature and role of the amyloid proteome in the manifestation, progression, and clearance of disease. Further exploration of the amyloid proteome may form the basis for the development of novel diagnostic tools, thereby enabling the development of novel therapeutic targets.

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