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bioRxiv · 10.1101/2025.01.30.635618

A-beta-induced distress of astrocytes triggers Alzheimer disease pathology through non-canonical delta secretase activity

Willnow, T.·Schmidt, V.·Malik, A.·Ziemlinska, E.·Obrebski, T.·Zurawska-Plaksej, E.·Cendrowski, J.·Hempstead, B. L.
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Abstract

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

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Willnow, T., Schmidt, V., Malik, A., Ziemlinska, E., Obrebski, T., Zurawska-Plaksej, E., Cendrowski, J., Hempstead, B. L.. 2025-01-31. A-beta-induced distress of astrocytes triggers Alzheimer disease pathology through non-canonical delta secretase activity. https://doi.org/10.1101/2025.01.30.635618

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