BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory

A Nash; HJM Gijsen; BJ Hrupka; KSL Teng; SF Lichtenthaler; H Takeshima; JM Gunnersen; KM Munro

Journal article

BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory

A Nash, HJM Gijsen, BJ Hrupka, KSL Teng, SF Lichtenthaler, H Takeshima, JM Gunnersen, KM Munro

Scientific Reports | NATURE PORTFOLIO | Published : 2021

DOI: 10.1038/s41598-021-94369-0

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Abstract

BACE inhibitors, which decrease BACE1 (β-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer’s disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4–8 weeks to achieve a clinically-relevant level of amyloid-β40 reduction in the brain. Mice u..

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University of Melbourne Researchers

Jenny Gunnersen Author

Kathryn Munro Author

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Grants

Awarded by Australian Research Council

Funding Acknowledgements

AN was supported by an Australian Government Research Training Program Scholarship. KMM was supported by a National Health and Medical Research Council-Australian Research Council Dementia Research Development Fellowship. This work was also funded by project grants from the Australian National Health and Medical Research Council to JMG (GNT10008046, GNT1058672, GNT1140050). This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, project ID 390857198). Student and post-doctoral exchanges were funded by Universities Australia (UA)-Deutsche Akademischer Austauschdienst (DAAD) to SFL, JMG and KMM.