Implications of Glycosylation in Alzheimer’s Disease

Haukedal, Henriette; Freude, Kristine

doi:10.3389/fnins.2020.625348

Cited by 74 publications

(80 citation statements)

References 116 publications

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“…This is consistent with earlier studies in mouse models, which show increases in CSF endogenous murine tau concentration without evidence of neuronal loss in APP transgenic mice [ 114 ]. In addition to phosphorylation, increasing evidence indicates that both N‐glycosylation and O‐glycosylation are implicated in AD, emphasized by the fact that tau carries potential N‐glycosylation and O‐glycosylation sites [ 115 ]. However, no established biomarkers to study the pathophysiological relevance of this in humans exist yet.…”

Section: Csf and Blood Biomarkers For Ad‐related Pathologiesmentioning

confidence: 99%

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease

et al. 2021

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Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust preanalytical protocols.

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Section: Csf and Blood Biomarkers For Ad‐related Pathologiesmentioning

confidence: 99%

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease

et al. 2021

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“…The exact structures of brain H5N4F1 peaks 1 and 3 have -to the best of the au-thors´ knowledge -not been reported so far. The decoration of the bisecting GlcNAc in human brain glycans may be of particular significance because GnT-III, which produces the bisecting structures, shows altered expression levels in Alzheimer disease (AD) patients 44,45 and other diseases 46 . Therefore, interest in this element experiences a renaissance 47 .…”

Section: Discussionmentioning

confidence: 99%

Time grid-based isomer specific N-glycan analysis and detection of bi-secting Lewis X in human brain

Helm

Gruber

Thader

et al. 2021

Preprint

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The importance of protein glycosylation in the biomedical field demands for methods capable of resolving and identifying isomeric structures of N-glycans. However, the unambiguous identification of isomeric structures from complex mixtures is currently not reasonably realized even by the most sophisticated approaches. Here we present a novel approach which uses stable isotope labelled reference N-glycans to establish a retention time grid (glyco-TiGr) on porous graphitized carbon. This furthermore enables retention as the primary criterion for the structural assignment of isomeric N-glycans. Moreover, we biosynthesized forty natural isomers of the fundamental N-glycan type consisting of five hexoses, four N-acetylhexosamines and one fucose residue. Nearly all of these isomers occupied unique positions on the retention time grid. Reference glycan assisted retention time determination with deci-minute accuracy narrowed the assignment space to very few, often only one possible glycan isomer. Application of the glyco-TiGr approach revealed yet undescribed isomers of Lewis x determinants in multimeric human IgA and hybrid type N-glycans in human brain with galactose and even fucose linked to the bisecting N-acetylglucosamine. Thus, the brain N-glycome displayed a degree of sophistication commensurate with this organ's role.

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“…Simulated inhibition of glycan biosynthesis pathway: Inhibition of all or parts of the glycosylation pathway is lately being considered a likely chemotherapeutic candidate for cancer (Kurosu, 2018) and Alzheimer's disease (Haukedal and Freude, 2020), and treatment of the novel coronavirus infection could also be approached in a similar way. There are established natural and synthetic inhibitors for blocking or slowing down the rate of glycosylation biosynthetic reactions (Jeffrey et al, 2015(Jeffrey et al, -2017.…”

Section: Methodsmentioning

confidence: 99%

N-Glycosylation Network Construction and Analysis to Modify Glycans on the Spike (S) Glycoprotein of SARS-CoV-2

Krishnan

2021

Front. Bioinform.

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Background: The N-glycan structure and composition of the spike (S) protein of SARS-CoV-2 are pertinent to vaccine development and efficacy.Methods: We reconstructed the glycosylation network based on previously published mass spectrometry data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 26 glycosyltransferase and glucosidase enzymes and could infer the pathway of glycosylation machinery based on glycans in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes—swainsonine or deoxynojirimycin for blocking mannosidase-II and indolizidine for blocking alpha-1,6-fucosyltransferase—to see how they would affect the biosynthesis network and the glycans that were synthesized.Results: The N-glycan biosynthesis network of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Of the 26 enzymes, the following were involved—Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B3GalT, B4GalT, Man-II, SiaT, ST3GalI, ST3GalVI, and FucT8. Blocking specific enzymes resulted in a substantially modified glycan profile of SARS-CoV-2.Conclusion: Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, are factors in the host response to the infection, vaccines, and antibodies. Heterogeneity in the N-glycan profile of the spike (S) protein and its potential effect on vaccine efficacy or adverse reactions to the vaccines remain unexplored. Here, we provide all the resources we generated—the glycans in the glycoCT xml format and the biosynthesis network for future work.

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Implications of Glycosylation in Alzheimer’s Disease

Cited by 74 publications

References 116 publications

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease

Time grid-based isomer specific N-glycan analysis and detection of bi-secting Lewis X in human brain

N-Glycosylation Network Construction and Analysis to Modify Glycans on the Spike (S) Glycoprotein of SARS-CoV-2

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