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5‐lipoxygenase as an endogenous modulator of amyloid beta formation in vivo
Author(s) -
Chu Jin,
Praticò Domenico
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22234
Subject(s) - creb , in vivo , downregulation and upregulation , endogeny , central nervous system , amyloid precursor protein , alzheimer's disease , neuroscience , amyloid beta , microbiology and biotechnology , chemistry , pathogenesis , amyloid (mycology) , biology , transcription factor , biochemistry , medicine , disease , gene , immunology , genetics , peptide , inorganic chemistry
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 β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches. Results 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. Interpretation 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