Contact Regions in the Dimer of Alzheimer β-Amyloid Domain [1–28] Studied by Mass Spectrometry

Li, Aiqun; Fenselau, Catherine

doi:10.1255/ejms.642

Cited by 6 publications

(8 citation statements)

References 75 publications

(222 reference statements)

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“…The conformational epitope of Ab1-28 could derive from tertiary or quaternary structure. It previously has been suggested (Li and Fenselau 2004) that Ab1-28 forms a dimer and when analyzed by SDS-PAGE ( Fig. 6b), our preparation migrates as a single band consistent with this suggestion.…”

Section: Conformational Nature Of Antibody Epitopesupporting

confidence: 91%

Monoclonal antibodies that target pathological assemblies of Aβ

Lambert

Velasco

Chang

et al. 2006

Journal of Neurochemistry

297

313

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Amyloid beta (Ab) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Ab oligomers (amyloid b-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Ab oligomers and fibrils but not the physiologically prevalent Ab monomer. Discrimination derived from an epitope found in assemblies of Ab1-28 and ADDLs but not in other sequences, including Ab1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Ab assemblies, these antibodies provide tools by which pathological Ab assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.

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Section: Conformational Nature Of Antibody Epitopesupporting

confidence: 91%

Monoclonal antibodies that target pathological assemblies of Aβ

Lambert

Velasco

Chang

et al. 2006

Journal of Neurochemistry

297

313

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“…Other MS studies carried out on shorter Ab models have yielded more structural information on Ab fibrillation. In this way, it was possible to identify which amino acid residues of Ab participate in interstrand pairing and initiate fibrillogenesis (Li & Fenselau, 2004), and to assess that Ab has a marked tendency for a parallel strand orientation that is strongly preferred over an antiparallel one (Jablonowska et al, 2004). HDX/MS has also been applied to investigate the different aggregation structures of Ab1-40, to highlight large differences between mature fibrils and protofibrils, and to demonstrate the possibility to rapidly and efficiently convert Ab1-40 monomers into clusters of protofibrils by the addition of some compounds such as calmidazolium chloride (Williams et al, 2005).…”

Section: Detection and Structural Analysis Of Abmentioning

confidence: 99%

The use of mass spectrometry to study amyloid‐β peptides

Grasso

2010

Mass Spectrometry Reviews

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Amyloid-β peptide (Aβ) varies in size from 39 to 43 amino acids and arises from sequential β- and γ-secretase processing of the amyloid precursor protein. Whereas the non-pathological role for Aβ is yet to be established, there is no disputing that Aβ is now widely regarded as central to the development of Alzheimer's disease (AD). The so named "amyloid cascade hypothesis" states that disease progression is the result of an increased Aβ burden in affected areas of the brain. To elucidate the Aβ role in AD, many analytical approaches have been proposed as suitable tools to investigate not only the total Aβ load but also many other issues that are considered crucial for AD, such as: (i) the aggregation state in which Aβ is present; (ii) its interaction with other species or metals; (iii) its ability to induce oxidative stress; and (iv) its degradative pathways. This review provides an insight into the use of mass spectrometry (MS) in the field of Aβ investigation aimed to assess its role in AD. In particular, the different MS-based approaches applied in vitro and in vivo that can provide detailed information on the above-mentioned issues are reviewed. Moreover, the advantages offered by the MS methods over all the other techniques are highlighted, together with the recent developments and uses of combined analytical approaches to detect and characterize Aβ.

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“…[26][27][28] More specific methodology based on mass spectrometry (MS) has been used to a limited extent for the analysis of Ab peptides in CSF. [29][30][31][32] For example, Lewczuk et al reported the existence of Ab 2-46 and Ab in CSF using surface-enhanced laser desorption/ ionization time-of-flight (SELDI-TOF)-MS. 32 Yuan and Desiderio used MS-based methodology in a peptidomics approach to biomarker discovery in CSF. 33 Other CSF peptides have been analyzed as biomarkers of AD.…”

Section: 15mentioning

confidence: 99%

“…System 3 was used to characterize the tryptic peptide fragments Ab 6-16 from MCO of Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and Ab . System 4 was used to characterize the tryptic peptide fragments Ab and Ab [29][30][31][32][33][34][35][36][37][38][39][40] from MCO of Ab .…”

Section: Liquid Chromatographymentioning

confidence: 99%

Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease

Inoue

Garner

Ackermann

et al. 2006

Rapid Comm Mass Spectrometry

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Alzheimer's disease is characterized by the deposition of senile plaques that consist primarily of amyloid beta peptides. There is substantial evidence that amyloid beta is oxidized in vivo, which has led to the suggestion that oxidative stress is an important mediator of Alzheimer's disease. Metal-catalyzed oxidation can mimic in vivo oxidation of amyloid beta because the metal ion binds to the amino acid residues at the site of oxidation, which then deliver reactive oxygen species to that site. Based on electrospray mass spectrometry, it has been suggested that metal-catalyzed oxidation occurs on histidines-13 and -14. Unfortunately, the amyloid beta peptides provide complex spectra, so it is difficult to definitively characterize the sites of oxidation. Trypsin digestion of both native and oxidized amyloid beta1-16 and amyloid beta1-40 resulted in the formation of tryptic peptides corresponding to amyloid beta6-16, which could be separated by liquid chromatography (LC). Sites of oxidation were then unequivocally characterized as histidine-13 and histidine-14 by LC/tandem mass spectrometric (MS/MS) analysis of the tryptic peptides. The ability to analyze the specific amyloid beta6-16 tryptic fragments derived from full-length amyloid beta peptides will make it possible to determine whether oxidation in vivo occurs at specific histidine residues and/or at other amino acid residues such as methionine-35. Using methodology based on LC/MS/MS it will also be possible to analyze the relative amounts of oxidized peptides and native peptide in cerebrospinal fluid from patients with Alzheimer's disease as biomarkers of oxidative stress.

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Contact Regions in the Dimer of Alzheimer β-Amyloid Domain [1–28] Studied by Mass Spectrometry

Cited by 6 publications

References 75 publications

Monoclonal antibodies that target pathological assemblies of Aβ

Monoclonal antibodies that target pathological assemblies of Aβ

The use of mass spectrometry to study amyloid‐β peptides

Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease

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