title: Inhibition of glutaminyl cyclase ameliorates amyloid pathology in an animal model of Alzheimer's disease via the modulation of γ-secretase activity.
abstract: Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid beta peptides are generated from amyloid beta precursor protein by consecutive catalysis by β and γ-secretases. Diversely modified forms of A have been N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length A. A previous study suggested that is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates-γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE 42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation , namely modulation of γ-secretase activity.
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Chang
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.forename: Sarah Kyua
authors.initials: SK
authors.lastname: Park
authors.forename: Phuong-Thao
authors.initials: PT
authors.lastname: Tran
authors.forename: Van-Hai
authors.initials: VH
authors.lastname: Hoang
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D053829:Amyloid Precursor Protein Secretases