Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.
The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3 × Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Jin
J
Chu
Jin-Guo
JG
Li
Domenico
D
Praticò
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016859:Lipoxygenase Inhibitors; D016875:tau Proteins; D001094:Arachidonate 5-Lipoxygenase; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases; C063449:zileuton; D006918:Hydroxyurea