Sugar Chains of Cerebrospinal Fluid Transferrin as a New Biological Marker of Alzheimer’s Disease

Abstract

Background/Aims: Alzheimer’s disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. Methods: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by lectin blotting using wheat germ agglutinin (WGA), and sugar chain analysis was performed by isoelectric focusing. Results: In Alzheimer’s CSF, several glycoproteins had lower WGA-binding activities, one of which was sufficiently sensitive and specific to distinguish AD from nondemented controls and other dementias. Further analysis identified this glycosylated protein as transferrin, and altered sugar chain composition of transferrin isoforms was observed despite normal protein levels in CSF. Conclusion: The decreased WGA-binding activity of transferrin in AD is probably due to altered glycosylation of transferrin molecules. Transferrin glycosylation is thus a potential biological marker for AD diagnosis, and changes in this glycosylation may play an important role in the pathophysiology of AD.

The role of protein glycosylation in Alzheimer disease

“…In contrast, the degree of sialylation of Tf is decreased in CSF. One report on CSF blots probed with the lectin WGA from AD patients, nondemented AD patients and nondemented controls revealed a lower degree of WGA-binding capacity in the CSF from AD patients, despite the fact that the levels of Tf protein were unaltered [10]. As WGA binds to sialic acid and GlcNAc, these data indicate altered glycosylation.…”

“…The roles of these O-glycans are elusive, although it has been proposed that APP processing by a-secretase, b-secretase and c-secretase occurs after O-glycosylation of APP, and that O-glycosylated APP is preferentially secreted [26,29]. Interestingly, a recent report demonstrated a new type of tyrosine O-glycosylation on short (Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] to Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] but not on full-length (Ab 1-38 to Ab 1-42 ) Ab fragments [27]. In a study using CSF from AD patients and nondemented controls, an increase in the short Ab fragments carrying the tyrosine-linked glycan was observed in AD patients.…”

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Serotransferrin (TF) glycosylation (Taniguchi et al, 2008) and aggregation (Booyjzsen et al, 2012) may play an important role in the pathophysiology of AD and also modulate the homeostasis of full-length APP (Khachaturian, 2008). Secretory carrierassociated membrane protein 1 (SCAMP1) and AP2-associated protein kinase 1 (AAK1) decreases the TF uptake by endocytosis suggesting their role in endocytosis via a mechanism, which may involve the recruitment of clathrin coats to the plasma membrane and the transGolgi network (Fernandez-Chacon et al, 2000, Conner andSchmid, 2002).…”

Quantitative Proteomics and Metabolomics Analysis of Normal Human Cerebrospinal Fluid Samples*

“…Active transport from blood and secretion from the brain contribute to the specific composition of CSF. This composition can be disturbed in neurological disorders (5)(6). Since CNS-specific proteins and metabolites are typically low in abundance compared with their levels in blood, this change in composition is more likely to be found in CSF because in blood the more abundant plasma proteins can completely mask the signal of the less abundant proteins.…”