N-glycan and Alzheimer's disease

Biochim Biophys Acta Gen Subj. 2017 Oct;1861(10):2447-2454. doi: 10.1016/j.bbagen.2017.04.012. Epub 2017 Apr 29.

Abstract

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), α-, β-, and γ-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.

Keywords: APP; Alzheimer's disease; BACE1; Bisecting GlcNAc; GnT-III; N-glycan.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Carbohydrate Sequence
  • Glycosylation
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Neprilysin / genetics
  • Neprilysin / metabolism
  • Polysaccharides / chemistry
  • Polysaccharides / metabolism*
  • Protein Processing, Post-Translational*
  • Proteolysis
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Signal Transduction
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • MAPT protein, human
  • Membrane Glycoproteins
  • Polysaccharides
  • Receptors, Immunologic
  • TREM2 protein, human
  • tau Proteins
  • Amyloid Precursor Protein Secretases
  • Neprilysin