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

K Zhu; X Xiang; S Filser; P Marinković; MM Dorostkar; S Crux; U Neumann; DR Shimshek; G Rammes; C Haass; SF Lichtenthaler; JM Gunnersen; J Herms

Journal article

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

K Zhu, X Xiang, S Filser, P Marinković, MM Dorostkar, S Crux, U Neumann, DR Shimshek, G Rammes, C Haass, SF Lichtenthaler, JM Gunnersen, J 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..

View full abstract

University of Melbourne Researchers

Jenny Gunnersen Author

Related Projects (6)

A POTENTIAL ANALGESIC TARGET IN A NOVEL CLINICALLY-RELEVANT NEUROPATHIC PAIN PATHWAY.

Persistent pain arising from tissue damage, to nerves, muscles or joints for example, is devastating for patients and a huge social and econ..

Impact of new Alzheimer's drugs on essential neuronal proteins

INVESTIGATING SECONDARY EFFECTS OF BACE1 INHIBITION, A PROMISING THERAPY FOR ALZHEIMER'S DISEASE

Synapses transfer information between neurons in the brain. In Alzheimer’s disease (AD), synapse loss results in dementia therefore it is im..

Function of the Alzheimer protease BACE1 in synapse development.

Searching for the “holy grail” of Alzheimer’s treatments: BACE inhibitors free of side-effects

SEZ6 and neuronal calcium signalling in synapse development

Inappropriate development and function of neuronal circuits is a universal feature of neurological disorders of cognition such as Down syndr..

Grants

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

Awarded by National Health and Medical Research Council

Awarded by National Health and Medical Research Council of Australia

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.