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

NEUROBIOLOGY OF AGING

卷:35

Article

Pratico, Domenico¹ 

[1] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA

关键词: Alzheimer's disease;    Amyloid beta;    Tau protein;    Transgenic mouse models;    5-Lipoxygenase;    Memory;   

DOI  :  10.1016/j.neurobiolaging.2014.05.016

来源: Elsevier

【 摘 要 】

The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12 months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid, and tau pathology assessed. Although mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significantly less A beta deposits and tau phosphorylation secondary to reduced gamma-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

Free