Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity
2017
The function of the
amyloid precursor protein(APP) in brain health remains unclear. This study elucidated a novel
cytoprotectivesignaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to
27-hydroxycholesterol(27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited
FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an
oxysterolstress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer’s Disease (AD) brains but not in
frontotemporal dementiabrains. These results unveil MAST4 as functional kinase of
FOXO1in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.
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