RETRACTED: Pharmacologic Inhibition of 5-Lipoxygenase Improves Memory, Rescues Synaptic Dysfunction, and Ameliorates Tau Pathology in a Transgenic Model of Tauopathy

Abstract

Background The 5-lipoxygenase (5LO) is a protein widely distributed in the central nervous system where modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer’s disease. However, no data are available as to whether 5LO is elevated in human tauopathy, or if it directly influences tau pathology in a relevant model of the disease. Methods We assayed 5LO levels in brain samples from tauopathy patients and transgenic tau mice, and evaluated the effect that 5LO pharmacological inhibition has on the phenotype of these mice. Results The 5LO is up-regulated in human tauopathy and transgenic tau mice brains. Pharmacological blockade of 5LO in tau mice results in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism. Conclusions Our results establish 5LO as a key player in the development of the tau pathology phenotype, and a novel viable therapeutic target for the pharmacological treatment of human tauopathy.

Extra-virgin olive oil ameliorates cognition and neuropathology of the 3xTg mice: role of autophagy

“…Immunoblot analyses were performed as previously described15, 16. Briefly, proteins were extracted in enzyme immunoassay buffer containing 250 mmol/L Tris base, 750 mmol/L NaCl, 5% NP‐40, 25 mmol/L EDTA, 2.5% sodium deoxycholate, 0.5% sodium dodecyl sulfate, and an EDTA‐free protease and phosphatase inhibitors cocktail tablet (Roche Applied Science, Indianapolis, IN, USA), sonicated, centrifuged at 56,700 g for 45 min at 4°C, and supernatants used for immunoblot analysis, as previously described.…”

“…Mouse brain homogenates were sequentially extracted first in RIPA buffer for the soluble and then in formic acid (FA) for the insoluble protein fraction as previously described15, 16. A β 1‐40 and A β 1‐42 levels were assayed by a sensitive sandwich ELISA kits (WAKO Chem., Richmond, VA).…”

“…Immunostaining was performed as reported previously 13, 14, 15, 16. Briefly, serial 6‐ μ m thick coronal sections were mounted on 3‐aminopropyl triethoxysilane‐coated slides.…”

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

“…The 5LO enzymatic pathway, which upon activation produces potent inflammatory mediators, has recently emerged as a novel target in neurodegeneration (Chu & Praticò, 2011b; Joshi et al ., 2014). Importantly, our group has shown that steady‐state levels of 5LO are increased in brain cortices from subjects with a postmortem diagnosis of PSP and that pharmacological inhibition of its activity ameliorates tau pathology and behavioral deficits in the htau mice (Giannopoulos et al ., 2015b). To gather further support and confirm that 5LO is indeed an active player in the tauopathy phenotype, in the current study, we implemented a different mouse model of tauopathy, the P301S line, and a new and opposite experimental approach, 5LO gene over‐expression, which by stably increasing the levels and activity of this pathway in the CNS of these mice, should exacerbate their pathological phenotype.…”

“…Previously, we showed that 5LO acts as an endogenous modulator of Aβ formation in vitro and in vivo by influencing the development of the AD‐like phenotype in transgenic mouse models of the disease (Firuzi et al ., 2008; Chu & Praticò, 2011a; Chu et al ., 2012a; Giannopoulos et al ., 2014). More recently, we reported that selective pharmacological inhibition of 5LO activity ameliorates tau neuropathology and behavioral impairments of htau mice, a transgenic mouse model expressing wild‐type human tau (Giannopoulos et al ., 2015b). …”