N-glycan and Alzheimer's disease

Background: Alzheimer's disease (AD) is a major form of dementia. Many evidence-based clinical trials have been performed, but no effective treatment has yet been developed. This suggests that our understanding of AD patho-mechanisms is still insufficient. In particular, the pathological roles of posttranslational modifications including glycosylation have remained poorly understood, but recent advances in glycobiology technology have gradually revealed that sugar modifications of AD-related molecules are profoundly involved in the onset and progression of this disease. Scope of review: We summarize the roles of N-glycans in AD pathogenesis and progression, particularly focusing on key AD-related molecules, including amyloid precursor protein (APP), alpha-, beta-, and gamma-secretases, and tau. Major conclusions: Biochemical, genetic and pharmacological studies have gradually revealed how N-glycans regulate AD development and progression through functional modulation of the key glycoproteins. These findings suggest that further glycobiology approaches in AD research will reveal novel glycan-based drug targets and early biomarkers of AD. However, N-glycan structures of these molecules in physiological and disease conditions and their precise functions are still largely unclear. Deeper glycobiology studies will be needed to reveal how AD pathology is regulated by glycosylation. General significance: It is now known that N-glycans play significant roles in AD development. However, specific pathological functions of particular glycan epitopes on each AD-related glycoprotein are still poorly understood. Future glycobiology studies with more sensitive glycoproteomic techniques and a wider variety of chemical glycosylation inhibitors could contribute to the development of novel glycan-based AD therapeutics. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.