title: O-linked β-N-acetylglucosaminidase inhibitor attenuates β-amyloid plaque and rescues memory impairment.
abstract: Deposition of β-amyloid (Aβ) 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 β-N-acetylglucosamine (O-GlcNAc) to proteins, and Aβ production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-α-d-glucopyranoso-[2,1-D]-Δ2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces Aβ production by lowering γ-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 γ-secretase. Moreover, NButGT attenuated the accumulation of Aβ, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between Aβ generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, Korea.
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Kim
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Nam
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Park
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Boo
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Jung
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Ju Yuel
authors.initials: JY
authors.lastname: Baek
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Cho
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000235:genetics; D014162:Transfection; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: C555050:1,2-dideoxy-2'-propylglucopyranoso(2,1-d)-delta 2'-thiazoline; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D053829:Amyloid Precursor Protein Secretases