RETRACTED ARTICLE: Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease

Abstract

The 5-Lipoxygenase (5LO) is upregulated in Alzheimer’s disease (AD), and in vivo modulates the amyloidotic phenotype of APP transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue we used a genetic and a pharmacologic approach by generating 3xTg mice deficient for 5LO, and administering 3xTg mice which a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life these mice had a significant reduction of Aβ and tau pathology.Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this proetin as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.

Neuroinflammation and Alzheimer’s disease: lessons learned from 5-lipoxygenase

“…We utilized We corroborated these findings of Aβ pathology in the 3xTg mouse and found that additionally, 5LO also acts on tau metabolism. Genetic unavailability of 5LO or its overexpression correlates directly with increased and diminished, respectively, tau phosphorylation, insoluble tau aggregation and NFT development [35,36]. We have shown that this aspect of 5LO is mediated by the cyclin-dependent kinase 5 (cdk5) [37].…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…In vivo overexpression of 5-LOX increases phosphorylation of specific Tau epitopes, and neuronal cells transfected with 5-LOX show a significant increase in tau phosphorylation even when their ability to generate Aβ is completely blocked, suggesting that the effect on tau is independent from Aβ (Chu et al, 2012). Interestingly, Tau-mice treated with zileuton (a potent 5-LOX inhibitor) displayed a significant improvement in memory and synaptic function together with a decreased tau phosphorylation level (Chu and Pratico, 2013;Giannopoulos et al, 2014). The use of PD146176, a specific 12/15 LOX inhibitor, also improved memory deficits and decreased Aβ plaques and neurofibrillary tangles in a genetic mice model of AD (Chu et al, 2015).…”

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

“…The 5‐lipoxygenase (5LO) is a pro‐inflammatory enzyme that by oxidizing free and esterified fatty acids produces potent bioactive lipids, most of which are grouped under the name of leukotrienes (LTs) (Giannopoulos, Chu et al., 2014; Giannopoulos, Joshi & Praticò, 2014). The protein is widely expressed in the central nervous system, where it localizes to both neuronal and glial cells.…”

“…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).…”