Transcriptional regulation of βsecretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments

Objective: 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. Methods: We investigated the molecular mechanism by which 12/15-LO regulates amyloid b ( Ab)/Ab precursor protein ( APP) metabolism in vivo and in vitro by genetic and pharmacologic approaches. Results: Here we show that overexpression of 12/15-LO leads to increased levels of b-secretase-1 ( BACE1) mRNA and protein, a significant elevation in Ab 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 Ab and BACE1 levels. Interpretation: 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.