Abstract
The function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling 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 oxysterol stress 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 dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.
Highlights
The biological function of the amyloid precursor protein (APP) as a signaling molecule in the brain remains unresolved, presenting a significant hurdle to understand its role in late-onset Alzheimer’s disease (AD) etiology[1,2,3]
Secreted lactate dehydrogenase (LDH) abundance from nd-SH-SY5Y cells (A) or B103 cells transfected with WT APP or empty vector (EV) (B), treated with 27OHC for 18 hours. (C) Live/dead analysis of B103 cells transfected with indicated vectors and treated as indicated. (D) Immunoblot of Caspases-7 and −3 in nd-SH-SY5Y cells treated as indicated. (E) Volcano plot of microarray data illustrating APP−/−/APP+/+ genotype fold changes in mouse brain cortex
The active intracellular domain (AICD)-MAST4 protective pathway was impaired in the brains of human late-onset AD, but not frontotemporal dementia (FTD) subjects, a neurodegenerative disease associated with genetic risk factors and unknown environmental causes[14]
Summary
The biological function of the amyloid precursor protein (APP) as a signaling molecule in the brain remains unresolved, presenting a significant hurdle to understand its role in late-onset Alzheimer’s disease (AD) etiology[1,2,3]. APP counters AD pathogenic triggers, such as oxidative stress, inflammation, and dyslipidemia, by transducing signals initiated by extracellular cholesterol stimuli to establish and maintain cellular cholesterol homeostasis[3,4,5,6] This downstream signaling is dependent upon the function of APP cleavage products, including the transcriptionally active amyloid intracellular domain (AICD)[7,8]. (J) Illustrated hypothesis for the effects of 5 or 50 μM 27OHC on APP, MAST4, FOXO1, and RTKN2. Intracellular domain (AICD) transactivated microtubule associated serine/threonine kinase family member 4 (MAST4), which phosphorylated and inhibited forkhead box protein O1 (FOXO1)-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival[11]. The AICD-MAST4 protective pathway was impaired in the brains of human late-onset AD, but not frontotemporal dementia (FTD) subjects, a neurodegenerative disease associated with genetic risk factors and unknown environmental causes[14]
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