Mass spectrometry analysis of the diversity of Aβ peptides: difficulties and future perspectives for AD biomarker discovery

Zakharova, Natalia V.; Бугрова, А. Е.; Kononikhin, Alexey; Indeykina, Maria I.; Popov, Igor; Nikolaev, Eugene

doi:10.1080/14789450.2018.1525296

Cited by 15 publications

(12 citation statements)

References 18 publications

(24 reference statements)

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“…Lastly, we found numerous spectral matches for Aβ that could only be observed exclusively by using FAIMS. These Aβ proteoforms, which typically require special fractionation or handling techniques in order to improve recovery due to their hydrophobic and aggregation prone-properties, 9, 16, 92, 93 were observed intact using FAIMS within the −40 to −50 CV range. This includes the canonical Aβ 1-42 and Aβ 1-40 ( Figure 11A and 11B , respectively), as well as several N-terminally truncated forms (specifically Aβ 2-42 and Aβ 4-42 , Figure 11C and 11D ).…”

Section: Resultsmentioning

confidence: 99%

“…6,7 Mass spectrometry has played a central role in these investigations, 8 particularly bottom-up approaches. [9][10][11][12][13][14][15][16] However, the protease digestion required for bottom-up analyses impedes the capturing of a protein's complete state, which can vary due to genetic alleles, alternative splicing, proteolytic processing, and post-translational modifications (referred to as "proteoforms"). [17][18][19][20] Since top-down proteomic (TDP) approaches analyze proteins in an intact state, the likelihood of capturing proteoforms associated with certain pathologies is greater and allows for a stronger, more direct connection between genotype and phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing top-down proteomics of brain tissue with FAIMS

Fulcher¹,

Makaju

Moore³

et al. 2021

Preprint

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Proteomic investigations of Alzheimer’s and Parkinson’s disease have provided valuable insights into neurodegenerative disorders. Thus far, these investigations have largely been restricted to bottom-up approaches, hindering the degree to which one can characterize a protein’s “intact” state. Top-down proteomics (TDP) overcomes this limitation, however it is typically limited to observing only the most abundant proteoforms and of a relatively small size. Therefore, offline fractionation techniques are commonly used to reduce sample complexity, limiting throughput. A higher throughput alternative is online fractionation, such as gas phase high-field asymmetric waveform ion mobility spectrometry (FAIMS). Utilizing a high complexity sample derived from Alzheimer’s disease brain tissue, we describe how the addition of FAIMS to TDP can robustly improve the depth of proteome coverage. For example, implementation of FAIMS at −50 compensation voltage (CV) more than doubled the mean number of non-redundant proteoforms observed (1,833 ± 17, n = 3), compared to without (754 ± 35 proteoforms). We also found FAIMS can influence the transmission of proteoforms and their charge envelopes based on their size. Importantly, FAIMS enabled the identification of intact amyloid beta (Aβ) proteoforms, including the aggregation-prone Aβ1-42 variant which is strongly linked to Alzheimer’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancing top-down proteomics of brain tissue with FAIMS

Fulcher¹,

Makaju

Moore³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…20 These exceptionally encouraging outcomes call for further examinations to assess plasma Ab as a screening tool for AD, including large-scale clinical studies and comparisons of various diagnostic methods for estimation of results. 21 With delicate and explicit enzyme-linked immunosorbent assay (ELISA), broad investigations of plasma A 1 b42 level and Ab 1 42/Ab 1 40 proportion were accounted during the improvement of plasma biomarkers. High proportions of plasma A 1 b42 expanded danger of AD.…”

Section: Discovery Of Different Plasma Biomarkers Using Proteomics Mmentioning

confidence: 99%

“…20 These exceptionally encouraging outcomes call for further examinations to assess plasma Aβ as a screening tool for AD, including large-scale clinical studies and comparisons of various diagnostic methods for estimation of results. 21…”

Section: Discovery Of Different Plasma Biomarkers Using Proteomics Mmentioning

confidence: 99%

Plasma Biomarkers: Potent Screeners of Alzheimer’s Disease

Naveed

Mubeen

Khan

et al. 2019

Am J Alzheimers Dis Other Demen

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Alzheimer’s disease (AD), a neurological disorder, is as a complex chronic disease of brain cell death that usher to cognitive decline and loss of memory. Its prevalence differs according to risk factors associated with it and necropsy performs vital role in its definite diagnosis. The stages of AD vary from preclinical to severe that proceeds to death of patient with no availability of treatment. Biomarker may be a biochemical change that can be recognized by different emerging technologies such as proteomics and metabolomics. Plasma biomarkers, 5-protein classifiers, are readily being used for the diagnosis of AD and can also predict its progression with a great accuracy, specificity, and sensitivity. In this review, upregulation or downregulation of few plasma proteins in patients with AD has also been discussed, when juxtaposed with control, and thus serves as potent biomarker in the diagnosis of AD.

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“…N-terminal truncated amyloid isoforms predominate in the insoluble material, while the C-terminal truncations are segregated into soluble aggregates [70]. Post-translational modifications include, besides others, pyro-glutamate (at position 3 or 11), truncation at Aβ4, and oxidation of methionine [58, 74].…”

Section: A Strategy To Develop Clinically Valuable Blood Protein Panementioning

confidence: 99%

Critical Steps to be Taken into Consideration Before Quantification of β-Amyloid and Tau Isoforms in Blood can be Implemented in a Clinical Environment

Vanderstichele¹,

Teunissen²,

Vanmechelen³

2019

Neurol Ther

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This review aims to document difficulties, limitations, and pitfalls when considering protein analysis in blood samples. It proposes an improved workflow for design, development, and validation of (immuno)assays for blood proteins, without providing reflections on a potential hypothesis of the origin of protein mismetabolism and deposition. There is a special focus on assay development for quantification of b-amyloid (Ab) and tau in blood for diagnostic use or for integration in clinical trials in the field of Alzheimer's disease (AD).

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Mass spectrometry analysis of the diversity of Aβ peptides: difficulties and future perspectives for AD biomarker discovery

Cited by 15 publications

References 18 publications

Enhancing top-down proteomics of brain tissue with FAIMS

Enhancing top-down proteomics of brain tissue with FAIMS

Plasma Biomarkers: Potent Screeners of Alzheimer’s Disease

Critical Steps to be Taken into Consideration Before Quantification of β-Amyloid and Tau Isoforms in Blood can be Implemented in a Clinical Environment

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