The Role of APP O-Glycosylation in Alzheimer's Disease

Abstract

The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer's disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.

Keywords: APP; O-glycan; ppGalNAc-T.

Figure 1

Schematic model of APP. Reported O-glycosylation sites and N-glycosylation sites are indicated. The O-glycan in brown means that these residues have been reported to have the potential to be modified by O-GlcNAc. Amino acid mutations labeled in green are mutations that affect β-cleavage. Mutations in blue affect γ-cleavage. Mutations in purple affect cohesiveness. The mutation in red is the Icelandic mutation (A673T). The pink dots indicate Ser or Thr residues that can be modified with O-glycans. The underlined Thr residue is O-glycosylated by ppGalNAc-T6.

Figure 2

Core structures of O-GalNAc glycans.

Figure 3

The expression of glycosyltransferases in AD brains by real-time PCR [67,75]. The results for isozymes in the ppGalNAc-T family and GnT-III are shown. Open circles indicate individual samples, and blue squares indicate average values for each group. eAD: early-stage AD.