2012
DOI: 10.1002/ana.22625
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Transcriptional regulation of βsecretase‐1 by 12/15‐lipoxygenase results in enhanced amyloidogenesis and cognitive impairments

Abstract: Objective The 12-15Lipoxygenase (12-15LO) is an enzyme widely distributed in the central nervous system and it has been involved in the neurobiology of Alzheimer’s disease (AD). However, the mechanism involved remains elusive. Methods We investigated the molecular mechanism by which 12-15LO regulates Amyloid β/APP metabolism in vivo and in vitro by genetic and pharmacologic approaches. Results Here we show that over-expression of 12-15LO leads to increased levels of BACE1 mRNA and protein, a significant el… Show more

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Cited by 31 publications
(35 citation statements)
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“…These include SP1, NF-B, YY1, HIF-1, PPAR␥, GADD153 (53), and Egr-1 (this study). SP1 binds to the BACE-1 promoter, induces BACE-1 expression in PC12 and HEK-293 cells (54), and mediates BACE-1 transcription induced by 12/15-lipoxygenase in the CNS (55). Likewise, NF-B acts as a repressor for BACE-1 transcription in differentiated neuronal cells and non-activated glia cells but as an activator in activated astrocytes and the A␤-exposed neuronal cultures (56).…”
Section: Discussionmentioning
confidence: 99%
“…These include SP1, NF-B, YY1, HIF-1, PPAR␥, GADD153 (53), and Egr-1 (this study). SP1 binds to the BACE-1 promoter, induces BACE-1 expression in PC12 and HEK-293 cells (54), and mediates BACE-1 transcription induced by 12/15-lipoxygenase in the CNS (55). Likewise, NF-B acts as a repressor for BACE-1 transcription in differentiated neuronal cells and non-activated glia cells but as an activator in activated astrocytes and the A␤-exposed neuronal cultures (56).…”
Section: Discussionmentioning
confidence: 99%
“…In the Tg2576 animals lacking 12/15LO, BACE-1 levels were reduced compared to Tg2576 animals with 12/15LO intact, mirroring the in vitro data [34]. By contrast, when Tg2576 mice were made to stably over-express 12/15LO they had a significant increase in Aβ peptides levels and deposition [36]. In vivo and in vitro studies showed that the effect of this enzymatic pathway on amyloidosis was indeed mediated by modulation of APP processing via the transcriptional regulation of BACE-1 mRNA levels, which involved the activation of the transcription factor Sp1 [36].…”
Section: Introductionmentioning
confidence: 57%
“…By contrast, when Tg2576 mice were made to stably over-express 12/15LO they had a significant increase in Aβ peptides levels and deposition [36]. In vivo and in vitro studies showed that the effect of this enzymatic pathway on amyloidosis was indeed mediated by modulation of APP processing via the transcriptional regulation of BACE-1 mRNA levels, which involved the activation of the transcription factor Sp1 [36]. In total, these data showed that this enzymatic pathway directly influences Aβ formation via a BACE-1 dependent mechanism, and that its pharmacological inhibition could represent a novel therapeutic target for AD.…”
Section: Introductionmentioning
confidence: 99%
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“…The expression of LOX is enhanced in the brain with aging and in models of neurodegeneration and inflammation (Uz et al, 1998; Manev et al, 2000b; Qu et al, 2000; Firuzi et al, 2008; Basselin et al, 2010). Recent studies related to CNS disease have focused primarily on the 5- and 12/15-LOX isozymes (Chu and Pratico, 2011; Hashimoto, 2011; Manev et al, 2011; Puccio et al, 2011; Chu et al, 2012a,b). The LOX isozymes catalyze stereospecific modification of AA at either carbon position 5, 12 or 15 or both 12 and 15, and the site of molecular oxygen insertion correspondingly defines the isozyme (i.e.…”
Section: Introductionmentioning
confidence: 99%