RETRACTED: 5-Lipoxygenase Activating Protein Reduction Ameliorates Cognitive Deficit, Synaptic Dysfunction, and Neuropathology in a Mouse Model of Alzheimer’s Disease

Abstract

Background 5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer’s disease (AD) with plaques and tangles (i.e., 3×Tg mice). Methods By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3×Tg mice. Results We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway. Conclusions Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.

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

“…Extracts from brain homogenates were used for biochemistry analyses, brain sections for immunohistochemistry as previously described (9, 11, 12, 14) (supplemental information). …”

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

“…Testing was always performed in the same room and at the same time to ensure environmental consistency as previously described (Di Meco, Lauretti, Vagnozzi & Praticò, 2014; Giannopoulos et al., 2013). Briefly, each mouse was placed in the center of the Y‐maze and allowed to explore freely during a 5‐min session as a measure of spontaneous alternating behavior.…”

“…To perform the Morris water maze (MWM), we used a white circular plastic tank (122 cm in diameter, walls 76 cm high), filled with water maintained at 22°±2°C, and made opaque by the addition of a nontoxic white paint, as previously described (Di Meco et al., 2014; Giannopoulos et al., 2013). Mice were trained on four consecutive days to find a Plexiglas platform submerged in water from four different starting points.…”

“…RIPA (radio immunoassay precipitation) extracts from mouse brain homogenates were used for Western blot analyses as previously described (Di Meco et al., 2014; Giannopoulos et al., 2013). Briefly, samples were electrophoresed on 10% Bis–Tris gels or 3%–8% Tris–acetate gel (Bio‐Rad, Richmond, CA, USA), transferred onto nitrocellulose membranes (Bio‐Rad), and then incubated overnight at 4°C with the appropriate primary antibodies; anti‐5LO [dilution: 1:200] (Santa Cruz, Dallas, TX, USA), anti‐HT7 [1:200] (Thermo, Waltham, MA, USA), anti‐AT8 [1:100] (Thermo), anti‐AT180 [1:200] (Thermo); anti‐AT270 [1:200] (Thermo), anti‐PHF1 (generous gift of Dr. Peter Davies); anti‐PHF13 [1:100 (Thermo)], anti‐SYP [1:300] (Santa Cruz), anti‐PSD95 [1:200] (Thermo), anti‐MAP2 [1:1,000] (Millipore), anti‐GSK3α/β [1:100] (Cell Signaling, Danvers, MA, USA), anti‐pGSK3α/β [1:100] (Cell Signaling), anti‐cdk5 [1:200] (Santa Cruz), anti‐p35/p25 [1:100] (Santa Cruz), anti‐GFAP (Santa Cruz), anti‐CD45 [1:100] (Thermo) and anti‐Beta actin [1:500] (Santa Cruz).…”

“…RIPA extracts from mouse brain homogenates were assayed for LTB4 levels using a specific LTB4 ELISA Kit (Enzo Life Sciences, Farmingdale, NY, USA) and following the instructions of the manufacturer (Di Meco et al., 2014; Giannopoulos et al., 2013). …”