Five lipoxygenase hypomethylation mediates the homocysteine effect on Alzheimer’s phenotype

Abstract

Environmental and genetic risk factors are implicated in the pathogenesis of Alzheimer’s disease (AD). However, how they interact and influence its pathogenesis remains to be investigated. High level of homocysteine (Hcy) is an AD risk factor and associates with an up-regulation of the ALOX5 gene. In the current paper we investigated whether this activation is responsible for the Hcy effect on the AD phenotype and the mechanisms involved. Triple transgenic mice were randomized to receive regular chow diet, a diet deficient in folate and B vitamins (Diet), which results in high Hcy, or the Diet plus zileuton, a specific ALOX5 inhibitor, for 7 months. Compared with controls, Diet-fed mice had a significant increase in Hcy levels, memory and learning deficits, up-regulation of the ALOX5 pathway, increased Aβ levels, tau phosphorylation, and synaptic pathology, which were absent in mice treated with zileuton. In vivo and vitro studies demonstrated that the mechanism responsible was the hypomethylation of the ALOX5 promoter. Our findings demonstrate that the up-regulation of the ALOX5 is responsible for the Hcy-dependent worsening of the AD phenotype in a relevant mouse model of the disease. The discovery of this previously unknown cross-talk between these two pathways could afford novel therapeutic opportunities for treating or halting AD.

Extra virgin olive oil improves synaptic activity, short‐term plasticity, memory, and neuropathology in a tauopathy model

“…The Y‐maze apparatus consisted of 3 arms, 32 cm (long) 610 cm (wide) with 26‐cm walls (San Diego Instruments, San Diego, CA). As previously described (Lauretti, Iuliano, et al, ; Li, Barrero, Merali, & Praticò, ), testing was always performed in the same room and at the same time to ensure environmental consistency. After introduction to the center of the Y‐maze, the animals freely explored the three arms for 5 min and the sequence and total number of arms entered was video‐recorded to calculate number of entries and percentage of alternation.…”

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

“…As previously described13, 14, testing was always performed in the same room and at the same time to ensure environmental consistency as previously described. After introduction to the center of the Y‐maze, the animal is allowed to freely explore the three arms for 5 min and the sequence and total number of arms entered was video‐recorded in order to calculate the percentage of alternation.…”

“…The fear conditioning test was performed in a conditioning chamber (19 × 25 × 19 cm) equipped with black methacrylate walls, transparent front door, a speaker, and grid floor (Start Fear System; Harvard Apparatus) as previously described 13. During the first day of the test, mice were placed into the conditioning chamber and allowed free exploration for 2 min in the white noise (65 dB) before the delivery of the conditioned stimulus (CS) tone (30 sec, 90 Db, 2000 Hz) paired with a foot‐shock unconditioned stimulus (2 sec, 0.6 mA) through a grid floor at the end of the tone.…”

“…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.…”

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

“…The assay for insoluble tau was performed as previously described (Li, Barrero, Merali & Praticò, 2017). Briefly, ultracentrifugation and sarkosyl extraction (30 min in 1% sarkosyl) were used to obtain soluble and insoluble fractions of tau from brain homogenates.…”