Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6

Kaichuan Zhu; Xianyuan Xiang; Severin Filser; Petar Marinkovic; Mario M Dorostkar; Sophie Crux; Ulf Neumann; Derya R Shimshek; Gerhard Rammes; Christian Haass; Stefan F Lichtenthaler; Jenny M Gunnersen; Jochen Herms

Journal article

Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibition Impairs Synaptic Plasticity via Seizure Protein 6

Kaichuan Zhu, Xianyuan Xiang, Severin Filser, Petar Marinkovic, Mario M Dorostkar, Sophie Crux, Ulf Neumann, Derya R Shimshek, Gerhard Rammes, Christian Haass, Stefan F Lichtenthaler, Jenny M Gunnersen, Jochen Herms

BIOLOGICAL PSYCHIATRY | ELSEVIER SCIENCE INC | Published : 2018

DOI: 10.1016/j.biopsych.2016.12.023

Abstract

BACKGROUND: Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a promising drug target for the treatment of Alzheimer's disease. Prolonged BACE1 inhibition interferes with structural and functional synaptic plasticity in mice, most likely by altering the metabolism of BACE1 substrates. Seizure protein 6 (SEZ6) is predominantly cleaved by BACE1, and Sez6 knockout mice share some phenotypes with BACE1 inhibitor-treated mice. We investigated whether SEZ6 is involved in BACE1 inhibition-induced structural and functional synaptic alterations. METHODS: The function of NB-360, a novel blood-brain barrier penetrant and orally available BACE1 inhibitor, was verified by immunoblotting. I..

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University of Melbourne Researchers

Jenny Gunnersen Author Anatomy and Physiology

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Grants

Awarded by Ludwig-Maximilians University Munich-China Scholarship Council Ph.D. Scholarship Program

Awarded by National Health and Medical Research Council

Funding Acknowledgements

KZ is supported by the Ludwig-Maximilians University Munich-China Scholarship Council Ph.D. Scholarship Program (File No. 201307650003). SFL is supported by the Helmholtz-Israel program and the Centers of Excellence in Neurodegeneration. JMG is supported by National Health and Medical Research Council Project Grants 1008046 and 1058672.