O-linked ¦Â-N-acetylglucosaminidase inhibitor attenuates ¦Â-amyloid plaque and rescues memory impairment

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• 作者：Chaeyoung Kim^a ; Dong Woo Nam^a ; Sang Yoon Park^b ; Hyundong Song^a ; Hyun Seok Hong^a ; ^c ; Jung Hyun Boo^a ; Eun Sun Jung^a ; Yoonhee Kim^a ; Ju Yuel Baek^d ; Kwan Soo Kim^d ; Jin Won Cho^b ; Inhee Mook-Jung^a ; ^{inhee@snu.ac.kr}
• 关键词：Alzheimer's disease (AD) ; ¦Â-Amyloid (A¦Â) ; O-GlcNAcylation ; 5XFAD transgenic mouse ; Nicastrin ; NButGT
• 刊名：Neurobiology of Aging
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：34
• 期：1
• 页码：275-285
• 全文大小：2548 K

文摘

Deposition of ¦Â-amyloid (A¦Â) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer's disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post-translational modification that adds O-linked ¦Â-N-acetylglucosamine (O-GlcNAc) to proteins, and A¦Â production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2¡ä-propyl-¦Á-d-glucopyranoso-[2,1-d]-¦¤2¡ä-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces A¦Â production by lowering ¦Ã-secretase activity both in vitro and in vivo. We also found that O-GlcNAcylation takes place at the S708 residue of nicastrin, which is a component of ¦Ã-secretase. Moreover, NButGT attenuated the accumulation of A¦Â, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between A¦Â generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.