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O-GlcNAcylation as a Therapeutic Target for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia and the number of elderly patients suffering from AD has been steadily increasing. Despite worldwide efforts to cope with this disease, little progress has been achieved with regard to identification of effective therapeutics. Thus, active research focusing on identification of new therapeutic targets of AD is ongoing. Among the new targets, post-translational modifications which modify the properties of mature proteins have gained attention. O-GlcNAcylation, a type of PTM that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to a protein, is being sought as a new target to treat AD pathologies. O-GlcNAcylation has been known to modify the two important components of AD pathological hallmarks, amyloid precursor protein, and tau protein. In addition, elevating O-GlcNAcylation levels in AD animal models has been shown to be effective in alleviating AD-associated pathology. Although studies investigating the precise mechanism of reversal of AD pathologies by targeting O-GlcNAcylation are not yet complete, it is clearly important to examine O-GlcNAcylation regulation as a target of AD therapeutics. This review highlights the mechanisms of O-GlcNAcylation and its role as a potential therapeutic target under physiological and pathological AD conditions.

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Abbreviations

AD:

Alzheimer’s disease

AGM:

N-acetylglucosamine phosphoglucomutase

AGX:

N-acetylglucosamine-1-phosphorylase

ALS:

Amyotrophic lateral sclerosis

APH-1:

Anterior pharynx-defective 1

APOE4:

Apolipoprotein E4

APP:

Amyloid precursor protein

ATP5A:

ATP synthase subunit α

Aβ:

Amyloid-beta

BACE1:

β-Secretase

BBB:

Blood brain barrier

CDK2:

Cyclin dependent kinase 2

CEBPβ:

CCAAT enhancer-binding protein β

CT:

Computerized tomography

EOAD:

Early onset AD

ER:

Endoplasmic reticulum

ERβ:

Estrogen receptor β

FAD:

Familiar AD

Fruc-6-P:

Fructose-6-phosphate

G6P-I:

Glucose-6-phosphate isomerase

GFAT:

Glutamine–fructose-6-phosphate-transaminase

Glc-6-P:

Glucose-6-phosphate

GlcN:

Glucosamine

GlcN-6-P:

GlcN-6-phosphate

GlcNAc:

N-acetylglucosamine

GlcNAc-1-P:

GlcNAc-1-phosphate

GlcNAc-6-P:

GlcNAc-6-phosphate

GLUT1:

Glucose transporter 1

GLUT3:

Glucose transporter 3

GNAT:

Glucosamine-6-phosphate acetyl transferase

GSK3β:

Glycogen synthase kinase 3β

HAT:

Histone acetyltransferase

HBP:

Hexosamine biosynthetic pathway

HD:

Huntington’s disease

HK:

Hexokinase

IR:

Insulin receptors

LOAD:

Late onset AD

lOGA:

Long OGA

MAPT:

Microtubule-associated protein tau

MCI:

Mild cognitive impairment

mOGT:

Mitochondrial OGT

MRI:

Magnetic resonance imaging

MTBRs:

Microtubule-binding repeats

NAC:

Non-amyloid β component

ncOGT:

Nucleocytoplasmic OGT

NFs:

Neurofilaments

NFTs:

Neurofibrillary tangles

nNOS:

Neuronal nitric oxide synthase

OGA:

O-GlcNAcase

O-GlcNAc:

O-linked β-N-acetylglucosamin

OGT:

O-GlcNAc transferase

PD:

Parkinson’s disease

PEN2:

Presenilin enhancer 2

PPO:

Phosphoinositide binding

PS1:

Presenilin1

PS2:

Presenilin2

PTMs:

Post-translational modifications

ROS:

Reactive oxygen species

sAPPα:

Soluble APPα

sAPPβ:

Soluble APPβ

SDS:

Sodium dodecyl sulfate

Ser:

Serine

SOD1:

Superoxide dismutase 1

sOGA:

Short OGA

sOGT:

Short OGT

T2DM:

Type 2 diabetes mellitus

Thr:

Threonine

TPR:

Tetratricopeptide repeat

UDP-GlcNAc:

Uridine diphosphate N-acetylglucosamine

XBP1:

X-box binding protein1

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Acknowledgements

This study was supported by Grants (2019R1A2C3011422, 2017M3C7A1048268, 2018M3C7A1021851) funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), the Ministry of Education, Science and Technology, Republic of Korea. The work was also supported by a grant to Korea Polar Research Institute (KOPRI) under project (PE20010).

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Authors and Affiliations

  1. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea

    Jinsu Park, Thiruma V. Arumugam & Dong-Gyu Jo

  2. Department of Health Science and Technology, Sungkyunkwan University, Seoul, 06351, Korea

    Jinsu Park & Dong-Gyu Jo

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Mitchell K. P. Lai

  4. Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, Singapore, 117593, Singapore

    Thiruma V. Arumugam

  5. Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Bundoora, VIC, Australia

    Thiruma V. Arumugam

  6. Biomedical Institute for Convergence, Sungkyunkwan University, Suwon, 16419, Korea

    Dong-Gyu Jo

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  1. Jinsu Park
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Correspondence to Thiruma V. Arumugam or Dong-Gyu Jo.

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Park, J., Lai, M.K.P., Arumugam, T.V. et al. O-GlcNAcylation as a Therapeutic Target for Alzheimer’s Disease. Neuromol Med 22, 171–193 (2020). https://doi.org/10.1007/s12017-019-08584-0

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