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
- Anna R. Malik
2025-10-31
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.