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

Heininger H, Feng X, Altunkaya A, Zheng F, Stockinger F, Wefers B, Müller SA, Giesbertz P, Tschirner SK, Shqau D, Adelsberger H, Ponomarenko A, Fenzl T, Alzheimer C, Lichtenthaler SF, Huth T (2025)

Publication Type: Journal article

Publication year: 2025

Journal

EMBO Reports EMBO Press

DOI: 10.1038/s44319-025-00604-4

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.

Authors with CRIS profile

Hannah Heininger Lehrstuhl für Physiologie Fang Zheng Lehrstuhl für Physiologie Florian Stockinger Department of Neurosurgery Alexey Ponomarenko Professur für Physiologie Christian Alzheimer Lehrstuhl für Physiologie Tobias Huth Lehrstuhl für Physiologie

Involved external institutions

Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Heininger, H., Feng, X., Altunkaya, A., Zheng, F., Stockinger, F., Wefers, B.,... Huth, T. (2025). BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions. EMBO Reports. https://doi.org/10.1038/s44319-025-00604-4

MLA:

Heininger, Hannah, et al. "BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions." EMBO Reports (2025).

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