Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer’s disease

Vanessa Schmidt (), Ewelina Ziemlinska, Tomasz Obrebski, Jemila P. Gomes, Ewa Zurawska-Plaksej, Jaroslaw Cendrowski, Johan Palmfeldt, Barbara L. Hempstead, Thomas E. Willnow () and Anna R. Malik ()
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Vanessa Schmidt: Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association
Ewelina Ziemlinska: University of Warsaw
Tomasz Obrebski: University of Warsaw
Jemila P. Gomes: Aarhus University
Ewa Zurawska-Plaksej: Wroclaw Medical University
Jaroslaw Cendrowski: International Institute of Molecular and Cell Biology
Johan Palmfeldt: Aarhus University
Barbara L. Hempstead: Weill Cornell Medical College
Thomas E. Willnow: Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association
Anna R. Malik: University of Warsaw

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The importance of astrocytes for Alzheimer’s disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway.

Date: 2025
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DOI: 10.1038/s41467-025-65536-y

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