N-terminal peptide fragment constitutes core of amyloid deposition of serum amyloid A: An imaging mass spectrometry study

Shintani-Domoto, Yukako; Ogawa, Masakata; Sugiyama, Eiji; Abé, Hiroyuki; Sakatani, Takashi; Ohashi, Ryuji; Ushiku, Tetsuo; Fukayama, Masashi

doi:10.1371/journal.pone.0275993

Cited by 4 publications

(2 citation statements)

References 37 publications

(49 reference statements)

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“…This profile is quite similar with APOE distribution. Although there are arguments that integrating these two data sets obtained from MALDI-MSI and LC-MS/MS need to be integrated, several lines of evidence including our previous study [ 35 ] and others [ 34 , 38 ] will convince pathological relevance of the current study.…”

Section: Discussionmentioning

confidence: 82%

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer’s Disease

Toyama,

Nirasawa,

Morishima

et al. 2024

Acta Histochem. Cytochem

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Pathological hallmark of Alzheimer’s disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. Clarification of the process of how soluble Aβ starts to assemble into amyloid fibrils is an essential step in elucidating the pathogenesis of AD. In our previous study, Aβ proteoforms including full-length Aβ40 and Aβ42/43 with N- and C-terminal truncated forms were visualized in postmortem brains from AD patients with matrix-assisted laser desorption/ionization-based mass spectrometry imaging (MALDI-MSI). In this study, Aβ proteoforms were consistently visualized by an updated protocol, and uncharacterized peptides such as Aβ1-29 and Aβ10-40 in AD brains were also visualized. To decipher neurotoxic effects of Aβ in patients’ brains, here we integrate liquid chromatography tandem mass spectrometry (LC-MS/MS) based shotgun proteomics with laser microdissection (LMD) excised tissue samples as well as direct tissue imaging with MALDI-MSI. With this approach, we have highlighted dynamic alterations of microtubule associating proteins (MAPs) including MAP1A, MAP1B and MAP2 as well as AD dominant proteins including APP, UCHL1, SNCA, and APOE. Of note, as lipid dysregulation has been implicated with AD pathology, we have challenged to integrate proteomics and lipid imaging for AD and control brain tissue. Spatial multi-omics is also valid to uncover molecular pathology of white matter as well as grey matter and leptomeningeal area, for example, by visualizing heme in patients’ postmortem brains.

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Section: Discussionmentioning

confidence: 82%

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer’s Disease

Toyama,

Nirasawa,

Morishima

et al. 2024

Acta Histochem. Cytochem

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“…Finally, a team in Japan reports that the SAA N-terminus 2-15 aa region promotes amyloid fibril formation upon investigation of the fragment isolated from human patients postmortem (Shintani-Domoto et al. 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region

Horgan,

Moore,

Fortin

2023

Veterinary Quarterly

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AA amyloidosis, characterized by the misfolding of serum amyloid A (SAA) protein, is the most common amyloid protein disorder across multiple species. SAA is a positive-acute phase protein synthesized by the liver in response to inflammation or stress, and it normally associates with high-density lipoprotein at its N-terminus. In this study, we focused on the 1-25 amino acid (aa) region of the complete 104 aa SAA sequence to examine the aggregation propensity of AA amyloid. A library comprising eight peptides from different species was assembled for analysis. To access the aggregation propensity of each peptide region, a bioinformatic study was conducted using the algorithm TANGO. Congo red (CR) binding assays, Thioflavin T (ThT) assays, and transmission electron microscopy (TEM) were utilized to evaluate whether the synthesized peptides formed amyloid-like fibrils. All synthetic SAA 1-25 congeners resulted in amyloid-like fibrils formation (per CR and/or ThT staining and TEM detection) at the exception of the ferret SAA1-25 fragment, which generated plaque-like materials by TEM. Ten residues were preserved among SAA 1-25 congeners resulting in amyloid-like fibrils, i.e. F6, E9, A10, G13, D16, M17, A20, Y21, D23, and M24. Amino acid residues highlighted by this study may have a role in increasing the propensity for amyloid-like fibril formation. This study put an emphasis on region 1-25 in the mechanism of SAA1 misfolding.

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Elucidation of the mechanism of amyloid A and transthyretin formation using mass spectrometry-based absolute quantification

et al. 2023

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Amyloidosis is triggered by the truncation of amyloid precursor proteins, causing organ damages. While previous studies found the truncation of amyloid A (AA) and amyloid transthyretin (ATTR) occurs in C- and N-terminal, respectively, the detailed mechanism of the fibril formation remains unclear. Liquid chromatography mass spectrometry is usually applied for a qualitative purpose, and thus quantification of tryptic peptide residue is difficult. We therefore employed a mass spectrometry-based quantification by isotope-labeled cell-free (MS-QBIC) to analyze the truncation processes in amyloid fibrillogenesis of AA and ATTR using the formalin-fixed paraffin-embedded tissues of autopsy cases. In this study, the process of transthyretin from an 'early fibril state' consisting of full-length ATTR to a 'mature ATTR amyloid fibril' with a truncated low-amyloidogenic segment has been mathematically revealed. The amount of full-length ATTR was nine times higher than in mature fibers. Large cohort studies using MS-QBIC may shed light on the clinical significance of amyloid fibrils.

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N-terminal peptide fragment constitutes core of amyloid deposition of serum amyloid A: An imaging mass spectrometry study

Cited by 4 publications

References 37 publications

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer’s Disease

Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer’s Disease

Investigation of serum amyloid a within animal species focusing on the 1-25 amino acid region

Elucidation of the mechanism of amyloid A and transthyretin formation using mass spectrometry-based absolute quantification

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