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Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice


Year of Publication:
Contact PI Name:
Domenico Pratico
Contact PI Affiliation:
Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
Antonio Di Meco, Elisabetta Lauretti, Alana N. Vagnozzi
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Art Quilt Initiative
National Institute on Aging (NIA)
Study Goal and Principal Findings:

5-Lipoxygenase (5LO) is an enzyme that catalyzes the conversion of arachidonic acid to 5-hydroxy-peroxy-eicosatetraenoic acid (5-HPETE) and subsequently to hydroxyl-eicotetraenoic acid (5-HETE), which can be then metabolized in different leukotrienes. It is widely expressed in the neuronal cells of the central nervous system, where its level increases in an age-dependent manner in the hippocampus and cortex, two brain regions prone to neurodegenerative insult. Previous work have shown that this pathway is up-regulated in AD patients, and that its genetic absence or over-expression modulates Aβ levels and tau metabolism in transgenic mouse models of the disease. Recent studies show that treatment with an orally available and specific inhibitor of 5LO, zileuton, at an early stage of the development of the AD- like phenotype delays cognition impairments, reduces amyloid beta (Aβ) levels, and tau phosphorylation in the same mouse models of AD.  The goal of this study was to test the efficacy and disease modifying properties of zileuton on behavioral and neuropathological hallmarks of late-stage AD. To this end the authors investigated the effect of zileuton on the late-stage, AD-like phenotype of the 3xTg mouse model. In this study, 12 month old 3xTg mice were dosed for 3 months with zileuton, or placebo. The data indicate that zileuton restores behavioral and cognitive function, significantly reduces Abeta deposition and tau hyperphosphorylation. In addition the data show that zileuton-mediated reduction in Abeta deposition and decreased tau phosphorylation are secondary to a gamma-secretase down regulation, and a decrease in the activation of CDK-5, respectively. The study provides further insights on the efficacy of 5LO pharmacologic inhibition as viable therapeutic approach for AD patients since it demonstrates that it has the potential to reverse all three of the most important aspects of the disease phenotype: memory decline, amyloid burden, and neurofibrillary tangles, after they are established.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
5-Lipoxygenase (ALOX5)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Y Maze
Contextual Fear Conditioning
beta Amyloid Load
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
A Disintegrin and Metalloproteinase Domain 10 (ADAM10)
gamma Secretase
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Amyloid Precursor Protein (APP)
Soluble Tau
Cyclin-Dependent Kinase 5 (CDK5)
GSK3 beta/phospho-GSK3 beta
p25/p35/Cyclin-Dependent Kinase 5 Regulatory Subunit 1 (CDK5R1)
Synaptic Proteins
Proinflammatory Markers
Target Engagement (Inhibition 5-Lipoxygenase)