Journal
FASEB JOURNAL
Volume 26, Issue 7, Pages 2930-2940Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-200295
Keywords
Alzheimer's disease; alpha-secretase; beta-secretase; developmental regulation
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Funding
- Alzheimer's Australia Research Viertel Fellowship
- NHMRC
- Australian Research Council
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Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the beta-amyloid (A beta) peptide is a central event in AD. While the pathway that generates A beta is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of alpha-secretase or beta-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.-Vella, L. J., Cappai, R. Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments. FASEB J. 26, 2930-2940 (2012). www.fasebj.org
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