BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions

The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

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Publication Details

Journal
EMBO Reports
Published
2025-11-20
DOI
https://doi.org/10.1038/s44319-025-00604-4
Citations
1
Primary Topic
Sleep and Wakefulness Research
Type
article
Field-Weighted Citation Impact
1.43

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article

BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions

Fang Zheng, Benedikt Wefers, Christian Alzheimer, Tobias Huth et al.
1 citations
EMBO Reports
Sleep and Wakefulness Research
1.43
article

BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions

Fang Zheng, Benedikt Wefers, Christian Alzheimer, Tobias Huth, Sarah K. Tschirner, Pieter Giesbertz, Helmuth Adelsberger, Stefan F. Lichtenthaler, Stephan A. Müller, Alp Altunkaya, Florian Stockinger, Thomas Fenzl, X. M. Feng, Hannah Heininger, Dorina Shqau, Alexey Ponomarenko
article en
1 citations

Abstract

The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.

EMBO ReportsVol. 27(1)
Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), German Center for Neurodegenerative Diseases (DE), Munich Cluster for Systems Neurology (DE), Bernstein Center for Computational Neuroscience Munich (DE), Technical University of Munich (DE)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Universitätsklinikum Erlangen
Openalex Percentile: Top 14%
Sleep and Wakefulness Research
1.43
DOIOpen Access PDFOpenAlex
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