Sialylation Fine-Tunes Glycoprotein Structural Microheterogeneity Associated with Alzheimer’s Disease as Captured by Native Ion Mobility-Mass Spectrometry

2020 ◽  
Author(s):  
Gongyu Li ◽  
Ashley Phetsanthad ◽  
Min Ma ◽  
Qinying Yu ◽  
Ashita Nair ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ion Mobility ◽  
Sialic Acids ◽  
Fine Tuning ◽  
Ion Mobility Mass Spectrometry ◽  
Structure Sensitive ◽  
Terminal Structure

Protein sialylation has been closely linked to many diseases including Alzheimer’s disease (AD) and is broadly implicated in therapeutics in a terminal structure-sensitive manner. However, how sialylation structurally affects mature glycoproteins and how such effect is linked biochemically to AD progression largely remain ill-defined and are, likely beset with the lack of appropriate strategies capable of rapid and in situ manipulation of sialic acids on mature glycoproteins. Herein, we report the use of native ion mobility-mass spectrometry (IM-MS)-based structural probing methodology, enabling well-controlled, synergistic and in situ manipulation of mature glycoproteins and attached sialic acids. Cell viability experiments and IM-MS suggest that the dysregulating effects of transferrin sialylation on the iron-enhanced Aβ cytotoxicity acts through sialylation-dependent Aβ and iron co-importing pathway. Meanwhile, native gel electrophoresis and IM-MS reveal the sialylation-regulated transferrin dimerization tendency. Collectively, IM-MS is adapted to capture key sialylation intermediates involved in fine-tuning AD-associated glycoprotein structural micoheterogeneity. Our results may shed new lights on AD-modifying strategies based on sialylation-regulated glycoprotein functions and cytotoxicity.

Sialylation Fine-Tunes Glycoprotein Structural Microheterogeneity Associated with Alzheimer’s Disease as Captured by Native Ion Mobility-Mass Spectrometry

2020 ◽  
Author(s):  
Gongyu Li ◽  
Ashley Phetsanthad ◽  
Min Ma ◽  
Qinying Yu ◽  
Ashita Nair ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ion Mobility ◽  
Sialic Acids ◽  
Fine Tuning ◽  
Ion Mobility Mass Spectrometry ◽  
Structure Sensitive ◽  
Terminal Structure

Protein sialylation has been closely linked to many diseases including Alzheimer’s disease (AD) and is broadly implicated in therapeutics in a terminal structure-sensitive manner. However, how sialylation structurally affects mature glycoproteins and how such effect is linked biochemically to AD progression largely remain ill-defined and are, likely beset with the lack of appropriate strategies capable of rapid and in situ manipulation of sialic acids on mature glycoproteins. Herein, we report the use of native ion mobility-mass spectrometry (IM-MS)-based structural probing methodology, enabling well-controlled, synergistic and in situ manipulation of mature glycoproteins and attached sialic acids. Cell viability experiments and IM-MS suggest that the dysregulating effects of transferrin sialylation on the iron-enhanced Aβ cytotoxicity acts through sialylation-dependent Aβ and iron co-importing pathway. Meanwhile, native gel electrophoresis and IM-MS reveal the sialylation-regulated transferrin dimerization tendency. Collectively, IM-MS is adapted to capture key sialylation intermediates involved in fine-tuning AD-associated glycoprotein structural micoheterogeneity. Our results may shed new lights on AD-modifying strategies based on sialylation-regulated glycoprotein functions and cytotoxicity.

scholarly journals Amyloid Plaque Polymorphism is Associated with Distinct Lipid Accumulations Revealed by Trapped Ion Mobility Mass Spectrometry Imaging (TIMS MSI)

2021 ◽  
Author(s):  
Wojciech Michno ◽  
Patrick Wehrli ◽  
Srinivas Koutarapu ◽  
Christian Marsching ◽  
Karolina Minta ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ion Mobility ◽  
Multimodal Imaging ◽  
Mass Spectrometry Imaging ◽  
Amyloid Plaque ◽  
Trapped Ion ◽  
Plaque Pathology ◽  
Lipid Species

Understanding of Alzheimer’s disease (AD) pathophysiology, requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids are particularly of interest as these are implicated in pathological- and neurodegenerative processes in AD. The exact molecular characteristics of the cellular environment in direct proximity to Aβ plaques are however still not known, not in the least due to high molecular complexity of lipid species but also due to the lacking spatial resolution, sensitivity, and specificity of analytical approaches. Likewise, how such micro environmental changes differ, across structurally polymorphic Aβ features - such as diffuse, immature and mature, fibrillary structures - has been a challenge, requiring complemental, multimodal imaging approaches. Herein, we used matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) trapped ion mobility spectrometry Time-of-Flight (TIMS TOF) in combination with hyperspectral microscopy to probe lipidomic microenvironment associated with structural polymorphism of Aβ plaque in transgenic mouse model of Alzheimer’s disease (tgAPPSWE).Integrated multivariate imaging data analysis revealed alteration of multiple lipid species showing a general, Aβ associated enrichment/depletion patterns. The hyperspectral imaging strategy further delineated unique distribution of PA, PE-Cer and PI lipids to more/less aggregated Aβ fibrillary structures present within individual Aβ plaques at different timepoints of progressing plaque pathology. Using an elaborate on tissue and ex situ validation approach, the unique possibility to obtain gas-phase isobar and isomer separations through TIMS TOF, facilitated unambiguous identification of lipid isomers that showed plaque pathology associated localizations. Finally, we followed AD pathology associated lipid changes over time, identifying plaque growth and maturation to be characterized by peripheral accumulation of PI (40:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for differentiation of both distinct lipid components in a complex micro environment, as well as their correlation to disease relevant amyloid plaque polymorphs.

scholarly journals Wie kleine Amyloid-β-Peptide zum großen Problem im Gehirn werden können

BIOspektrum ◽  
2021 ◽  
Vol 27 (7) ◽  
pp. 705-708
Author(s):  
René Zangl ◽  
Nina Morgner
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Properties ◽  
Ion Mobility Spectrometry ◽  
Ion Mobility ◽  
Amyloid Β ◽  
Amyloid Β Peptide

AbstractThe formation of amyloid-β oligomers plays a key role in the onset of Alzheimer’s disease. We investigated the aggregation of amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing those structural properties, which lead to the formation of mature fibrils. We can show that the arrangement of the first oligomers is crucial for the topology of the resulting species, leading to the formation of non-toxic aggregates or fibrils.

Rapid Diagnosis of Parkinson’s Disease from Sebum using Paper Spray Ionisation Ion Mobility Mass Spectrometry

2020 ◽  
Author(s):  
Depanjan Sarkar ◽  
Drupad Trivedi ◽  
Eleanor Sinclair ◽  
Sze Hway Lim ◽  
Caitlin Walton-Doyle ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ion Mobility ◽  
Neurodegenerative Disorder ◽  
Treatment Options ◽  
Ion Mobility Mass Spectrometry ◽  
Paper Spray ◽  
Molecular Features ◽  
Validation Set

Parkinson’s disease (PD) is the second most common neurodegenerative disorder for which identification of robust biomarkers to complement clinical PD diagnosis would accelerate treatment options and help to stratify disease progression. Here we demonstrate the use of paper spray ionisation coupled with ion mobility mass spectrometry (PSI IM-MS) to determine diagnostic molecular features of PD in sebum. PSI IM-MS was performed directly from skin swabs, collected from 34 people with PD and 30 matched control subjects as a training set and a further 91 samples from 5 different collection sites as a validation set. PSI IM-MS elucidates ~ 4200 features from each individual and we report two classes of lipids (namely phosphatidylcholine and cardiolipin) that differ significantly in the sebum of people with PD. Putative metabolite annotations are obtained using tandem mass spectrometry experiments combined with accurate mass measurements. Sample preparation and PSI IM-MS analysis and diagnosis can be performed ~5 minutes per sample offering a new route to for rapid and inexpensive confirmatory diagnosis of this disease.

Application of mass spectrometry-based chromatographic technologies in the diagnosis of Alzheimer’s disease

2011 ◽  
Vol 29 (4) ◽  
pp. 293-297
Author(s):  
Dingqian WANG ◽  
Guizhong XIN ◽  
Ziqi SHI ◽  
Jun CHEN ◽  
Ping LI
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease
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