TY  - JOUR
AU  - Heininger, Hannah
AU  - Feng, Xiao
AU  - Altunkaya, Alp
AU  - Zheng, Fang
AU  - Stockinger, Florian
AU  - Wefers, Benedikt
AU  - Müller, Stephan A
AU  - Giesbertz, Pieter
AU  - Tschirner, Sarah
AU  - Shqau, Dorina
AU  - Adelsberger, Helmuth
AU  - Ponomarenko, Alexey
AU  - Fenzl, Thomas
AU  - Alzheimer, Christian
AU  - Lichtenthaler, Stefan F
AU  - Huth, Tobias
TI  - BACE1 regulates sleep–wake cycle through both enzymatic and non–enzymatic actions
JO  - EMBO reports
VL  - Advance online publication
SN  - 1469-221X
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2025-01399
SP  - -
PY  - 2025
AB  - 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.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s44319-025-00604-4
UR  - https://pub.dzne.de/record/282938
ER  -