5-lipoxygenase as an endogenous modulator of amyloid beta formation in vivo
Article first published online: 17 NOV 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 69, Issue 1, pages 34–46, January 2011
How to Cite
Chu, J. and Praticò, D. (2011), 5-lipoxygenase as an endogenous modulator of amyloid beta formation in vivo. Ann Neurol., 69: 34–46. doi: 10.1002/ana.22234
- Issue published online: 28 JAN 2011
- Article first published online: 17 NOV 2010
- Manuscript Accepted: 20 AUG 2010
- Manuscript Revised: 4 AUG 2010
- Manuscript Received: 30 JUN 2010
- National Institutes of Health (NIH)
- National Institute on Aging. Grant Numbers: AG-022152, AG-033568
- Alzheimer's Association Zenith Fellowship. Grant Number: ZEN-07-59289
The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is upregulated in Alzheimer's disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive.
We evaluated the molecular mechanism by which 5-LO regulates amyloid β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches.
Here we show that 5-LO regulates the formation of Aβ by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the γ-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of Aβ formation and the increase of γ-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Aβ, CREB and γ-secretase levels.
These data establish a novel functional role for 5-LO in regulating endogenous formation of Aβ levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer's disease. Ann Neurol 2010