Transcriptional regulation of βsecretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments
Version of Record online: 24 JAN 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 1, pages 57–67, January 2012
How to Cite
Chu, J., Zhuo, J.-M. and Praticò, D. (2012), Transcriptional regulation of βsecretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments. Ann Neurol., 71: 57–67. doi: 10.1002/ana.22625
- Issue online: 24 JAN 2012
- Version of Record online: 24 JAN 2012
- Accepted manuscript online: 12 SEP 2011 08:28AM EST
- Manuscript Accepted: 2 SEP 2011
- Manuscript Revised: 23 AUG 2011
- Manuscript Received: 27 JUL 2011
- National Institute of Aging (NIH). Grant Number: AG33568
- Alzheimer association. Grant Number: NPSP-10-170775
12/15-Lipoxygenase (12/15-LO) is an enzyme widely distributed in the central nervous system, and it has been involved in the neurobiology of Alzheimer disease (AD). However, the mechanism involved remains elusive.
We investigated the molecular mechanism by which 12/15-LO regulates amyloid β (Aβ)/Aβ precursor protein (APP) metabolism in vivo and in vitro by genetic and pharmacologic approaches.
Here we show that overexpression of 12/15-LO leads to increased levels of β-secretase-1 (BACE1) mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice. In vitro and in vivo studies demonstrate that 12/15-LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12/15-LO–overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15-LO–deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant-negative mutant blocks the 12/15-LO–dependent elevation of Aβ and BACE1 levels.
Our findings demonstrate a novel pathway by which 12/15-LO increases the amyloidogenic processing of APP through a Sp1-mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy. ANN NEUROL 2012;71:57–67