Affiliations: [a] Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea | [b] Case School, 1960 Cate Mesa Road Carpinteria, CA 93013, USA | [c] Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, Korea
Correspondence:
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Correspondence to: Inhee Mook-Jung, Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea. Tel.: +82 2 740 8245; Fax: +82 2 3672 7352; E-mail: inhee@snu.ac.kr.
Note: [1] These authors contributed equally to this work.
Abstract: Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid-β peptides (Aβ) are generated from amyloid-β precursor protein by consecutive catalysis by β- and γ-secretases. Diversely modified forms of Aβ have been discovered, including pyroglutamate Aβ (N3pE-42 Aβ). 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 Aβ. A previous study suggested that N3pE-42 Aβ formation 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.
