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Review
. 2019 Sep 3;6(3):92.
doi: 10.3390/medicines6030092.

Early Stage Glycosylation Biomarkers in Alzheimer's Disease

Patricia Regan  1   2 , Paula L McClean  3 , Thomas Smyth  4   5 , Margaret Doherty  4   5
Affiliations
Review

Early Stage Glycosylation Biomarkers in Alzheimer's Disease

Patricia Regan et al. Medicines (Basel). .

Abstract

Alzheimer's disease (AD) is of great cause for concern in our ageing population, which currently lacks diagnostic tools to permit accurate and timely diagnosis for affected individuals. The development of such tools could enable therapeutic interventions earlier in the disease course and thus potentially reducing the debilitating effects of AD. Glycosylation is a common, and important, post translational modification of proteins implicated in a host of disease states resulting in a complex array of glycans being incorporated into biomolecules. Recent investigations of glycan profiles, in a wide range of conditions, has been made possible due to technological advances in the field enabling accurate glycoanalyses. Amyloid beta (Aβ) peptides, tau protein, and other important proteins involved in AD pathogenesis, have altered glycosylation profiles. Crucially, these abnormalities present early in the disease state, are present in the peripheral blood, and help to distinguish AD from other dementias. This review describes the aberrant glycome in AD, focusing on proteins implicated in development and progression, and elucidates the potential of glycome aberrations as early stage biomarkers of AD.

Keywords: Alzheimer’s; Aβ; biomarker; glycosylation; tau.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
N-glycan profiling of a glycoprotein mixture. N-linked glycans are cleaved from glycoproteins by PNGase F digestion and fluorescently labelled in preparation for exoglycosidase sequencing and subsequent ultra-high performance liquid chromatography (UPLC) analysis. Terminal monosaccharides are removed from the non-reducing end of a glycan structure during an exoglycosidase digestion. Black dotted lines indicate the points of enzymatic digestion in this example of an exoglycosidase digestion. ASN, Asparagine residue in a protein chain; UPLC, ultra high performance liquid chromatography; PNGase F, peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase. Images were created using Adobe Photoshop.
Figure 2
Figure 2
Examples of glycan alterations in disease related glycoproteins in Alzheimer’s disease (AD). (A) Tau, a central protein in the AD pathology, is O-GlcNAcylated which acts as a defense against hyperphosphorylation. In AD, O-glycosylation is downregulated and tau becomes uncharacteristically N-glycosylated. Both normal and hyperphosphorylated tau contain N-glycans in AD. Truncated glycans are more abundant on paired helical filaments (PHF) which are present later in the disease pathology. (B) Bisecting GlcNAc on β-secretase β-site APP-cleaving enzyme 1 (BACE1) occurs prior to toxic Aβ formation in AD. In contrast, GlcNAc bisection on amyloid precursor protein (APP) stimulates α-secretase production and acts as a protective mechanism against amyloid beta (Aβ) peptide formation (not shown). (C) Decreased terminal sialic acids are present on AD cerebrospinal fluid (CSF) glycoproteins, the major glycoprotein being transferrin which is critical to the survival of neuronal cells. Additionally, BACE1 and presenilin, a subunit of γ-secretase, both have a direct role in the sialylation of AD relevant proteins. Grey dotted lines indicate location of changes on glycan structures. Alzheimer’s disease, AD; N-acetyl glucosamine, GlcNAc; amyloid beta, Aβ; amyloid precursor protein, APP; cerebrospinal fluid, CSF; β-site APP-cleaving enzyme 1, BACE1; SER, serine; THR, threonine; ASN, asparagine; pTau, hyperphosphorylated tau; PHF, paired helical filaments. Images were created using Adobe Photoshop.
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