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

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.