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Notice of Special Interest (NOSI): Deciphering the Glycosylation Code of Alzheimer's Disease

National Institutes of Health

Glycosylation is a post-translational modification in which a sugar (or carbohydrate) is attached to a hydroxyl or other functional group of a macro molecule (such as DNA, lipids and proteins). Most glycosylated proteins are glycosylated in the rough endoplasmic reticulum (ER) or Golgi by glycosyltransferases. Likewise, specific serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins can be modified by N-acetylglucosamine (O-GlcNAc) transferase (OGT), which adds a single sugar N-acetylglucosamine. Glycosylation is known to affect various cellular and physiological functions including regulation of enzymatic activities, cell differentiation and morphogenesis.

Currently, approaches for both basic and clinical biology of Alzheimer's disease (AD) are largely focused on disease-related changes at the genomic, epigenetic, transcriptomic, and proteomic level(s). However, there are many different aspects of biology and cellular biochemistry that cannot be explained by these types of systems approaches. Glycosylation and complex carbohydrates have been reported to play many critical roles in the early pathogenesis and progression of AD, but the potential of these molecules to serve as biomarkers and targets of disease intervention remains largely unexplored.

Recent studies have also suggested that the deficiency of a sulfotransferase for sialic acid-modified glycan could mitigate AD pathology and binding of Aß to various AD-risk glycoproteins such as TREM2, which are likely regulated by the change of glycans on these molecules as well. Small molecules that are known to block the interactions of Aß and glycans have been shown to increase survival advantage of neurons in mouse models of AD. Together, these findings indicate the potential of glycomic aberrations as potential biomarkers and targets of disease prevention. Despite the importance of glycosylation and altered glycan structures in AD, the aberrant molecular and biochemical function of these glycosylated molecules to serve as disease modifiers remain largely elusive.

Traditionally, it has been very difficult to study and monitor the alteration of glycosylation and glycans in relation to aging and early initiation of AD. However, several recently developed technologies now allow one to systematically monitor the change of protein glycosylation and glycans in various biological fluids from a large number of individuals. Therefore, the goal of this Notice of Special Interest (NOSI) is to invite research projects using state-of-the-art methods of protein carbohydrate analyses to understand the potential impact of glycosylation on the etiology of AD and biomarker discovery.

This notice applies to due dates on or after March 11, 2022 and subsequent receipt dates through November 13, 2024.

Application Due Date(s): March 11, 2022; July 8, 2022; Nov 14, 2022; March 10, 2023; July 10, 2023; Nov 13, 2023; March 11, 2024; July 9, 2024; Nov 12, 2024

NOT-AG-21-042