5-Lipoxygenase as an Endogenous Modulator of Amyloid β Formation In Vivo

Objective: 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. Methods: We evaluated the molecular mechanism by which 5-LO regulates amyloid beta (A beta) formation in vitro and in vivo by pharmacological and genetic approaches. Results: Here we show that 5-LO regulates the formation of A beta by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the gamma-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of A beta formation and the increase of gamma-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of A beta, CREB and gamma-secretase levels. Interpretation: These data establish a novel functional role for 5-LO in regulating endogenous formation of A beta 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 2011;69:34-46