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Exp Gerontol. 2014 Oct;58:198-202. doi: 10.1016/j.exger.2014.08.008. Epub 2014 Aug 19.

The mitochondrial O-linked N-acetylglucosamine transferase (mOGT) in the diabetic patient could be the initial trigger to develop Alzheimer disease.

Author information

1
National Autonomous University of Mexico, Department of Biochemistry, Faculty of Medicine, Mexico.
2
National Institute of Respiratory Diseases, "Ismael Cosío Villegas", Mexico.
3
National Institute of Respiratory Diseases, "Ismael Cosío Villegas", Mexico. Electronic address: nnooee@gmail.com.

Abstract

Diabetes mellitus (DM) is considered a risk factor for the development of Alzheimer disease (AD); however, how DM favors evolution of AD is still insufficiently understood. Hyperglycemia in DM is associated to an increase in mitochondrial reactive oxygen species (ROS) generation, as well as damage of hippocampal cells, reflected by changes in morphological and mitochondrial functionality. Similar mitochondrial damage has been observed when amyloid beta (Aβ) accumulates in the brain of AD patients. In DM, the excess of glucose in the brain induces higher activity of the hexosamine biosynthesis pathway (HBP), it synthesizes UDP-N-acetylglucosamine (UDP-GlcNAc), which is used by O-linked N-acetylglucosamine transferase (OGT) to catalyze O-GlcNAcylation of numerous proteins. Although O-GlcNAcylation plays an important role in maintaining structure and cellular functionality, chronic activity of this pathway has been associated with insulin resistance and hyperglycemia-induced glucose toxicity. Three different forms of OGT are known: nucleocytoplasmic (ncOGT), short (sOGT), and mitochondrial (mOGT). Previous reports showed that overexpression of ncOGT is not toxic to the cell; in contrast, overexpression of mOGT is associated with cellular apoptosis. In this work, we suggest that hyperglycemia in the diabetic patient could induce greater expression and activity of mOGT, modifying the structure and functionality of mitochondria in hippocampal cells, accelerating neuronal damage, and favoring the start of AD. In consequence, mOGT activity could be a key point for AD development in patients with DM.

KEYWORDS:

Alzheimer disease; Diabetes mellitus; Mitochondria; O-GlcNAcylation; O-glycosyl transferase

PMID:
25148700
DOI:
10.1016/j.exger.2014.08.008
[Indexed for MEDLINE]

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