Zileuton Improves Memory Deficits, Amyloid and Tau Pathology in a Mouse Model of Alzheimer’s Disease with Plaques and Tangles

Abstract

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.

Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice

“…The dose of the drug selected in this study was based on our previous work, showing that this concentration of drug significantly reduces 5LO activation (Chu et al., 2013). As shown in Figure 2, no significant differences were observed between the P301S control group and P301S mice receiving zileuton when steady‐state levels of brain 5LO protein were assayed.…”

“…In our study, mice were exposed to the drug ad libitum as it was dissolved in their drinking water, and based on the daily consumption of water of approximately 5 ml, we were confident that, as in our previous studies, they were exposed to a therapeutic dose of zileuton (Chu et al., 2013). To confirm compliance with the treatment as well as target engagement, we assessed brain levels of LTB4, the major metabolic product of 5LO enzymatic activation, and found that indeed it was reduced by almost 80%.…”

“…Two separate groups of 3‐month‐old WT and P301S mice were randomized to receive zileuton (200 mg/L) or vehicle in their drinking water three times per week over 7 months ( n  = 10 per group; 5 males, 5 females). This amount of the drug was selected based on our previous work where we showed that it significantly reduced 5LO activation (Chu et al., 2013). After the treatment period and at 10 months of age, the mice underwent behavioral tests as described below.…”

“…The protein is widely expressed in the central nervous system, where it localizes to both neuronal and glial cells. Previously, our group has demonstrated a role for 5LO in the development of the AD‐like phenotype of APP transgenic mice and related tauopathy as well as the triple transgenic mice, which are known to develop both Aβ plaques and tau tangles (Chu, Giannopoulos, Ceballos‐Diaz, Golde & Pratico, 2012; Chu, Li & Pratico, 2013; Giannopoulos, Chu et al., 2014; Giannopoulos et al., 2015; Giannopoulos, Joshi & Praticò, 2014; Joshi, Chu & Praticò, 2013). More recently, we showed that genetic deficiency for 5LO rescued behavioral deficits and tau phosphorylation, as well as synaptic pathology and neuroinflammation in the P301S mice (Vagnozzi, Giannopoulos & Praticò, 2017).…”

Arachidonic acid in Alzheimer's disease

“…But the use of 5-LOX inhibitors demonstrated that 5-LOX and its products have a stronger impact on Aβ peptide production and tau phosphorylation in neuronal cells 37 than in the proliferation of glial cells and neuroinflammation.…”