RETRACTED ARTICLE: Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway

Abstract

Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.

RETRACTED ARTICLE: VPS35 regulates tau phosphorylation and neuropathology in tauopathy

“…RIPA extracts from human and mouse brain homogenates were used for Western Blot analyses as previously described [16,23]. Briefly, samples were electrophoresed on 10% Bis-Tris gels or 3-8% Tris-acetate gel (Bio-Rad, Richmond, CA), transferred onto nitrocellulose membranes (Bio-Rad), and then incubated overnight at 4° C with the appropriate primary antibodies; anti-VPS35 [dilution: 1:300] (Abcam, Cambridge), anti-VPS26 [dilution: 1:200 ), membranes were incubated with IRDye 800CW-labeled secondary antibodies (LI-COR Bioscience, Lincoln, NE) at room temperature for 1 h. Signals were developed with Odyssey Infrared Imaging Systems (LI-COR Bioscience, Lincoln, Nebraska).…”

Improved Bioavailability of Montelukast through a Novel Oral Mucoadhesive Film in Humans and Mice

“…Secondly, we analyzed pharmacokinetics of MTK in a transgenic mouse model of AD, because recently it was shown that pharmacological inhibition of leukotriene signaling had beneficial effects in several mouse models of AD [30][31][32][33][34]. The leukotriene receptor antagonist MTK has been proposed as an interesting candidate for drug repurposing in AD patients [13][14][15], due to its potential to modulate neuroinflammation and improve memory in animal models of stroke [35], epilepsy [36,37] and Lewy body dementia [38].…”

AMI, an Indazole Derivative, Improves Parkinson’s Disease by Inhibiting Tau Phosphorylation

“…Consistent with previous studies, our results showed that AMI inhibits the expression of the tau upstream kinase GSK-3β. In addition, tau protein kinase II (TPKII) formed by a complex containing two subunits of Cyclin-dependent Kinase 5 (CDK5) and p35 can synergistically increase the efficiency of GSK-3β phosphorylation of tau protein (Xiao et al, 2018;Giannopoulos et al, 2019). Therefore, we need to investigate the expression of tau protein kinase II (TPKII) in the next experiment.…”