Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway
Authors: Domenico Praticò
Jian Chiu
Phillip F Giannopoulos
Journal: Molecular Neurobiology (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Behavior; Five-lipoxygenase; Leukotrienes; Neuroinflammation; Tauopathy
Affiliations: Alzheimer's Center at Temple, Lewis Katz School of Medicine, Scott Richards North Star Foundation Chair, Alzheimer's Research, Temple University, 947, Medical Education and Research Building, 3500 North Broad Street, Philadelphia, PA, 19140, USA., Alzheimer's Center at Temple, Lewis Katz School of Medicine, Scott Richards North Star Foundation Chair, Alzheimer's Research, Temple University, 947, Medical Education and Research Building, 3500 North Broad Street, Philadelphia, PA, 19140, USA. .

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: No

PubPeer comments:
 Fig 3C.  Suppression of lncRNA UCA triggers apoptosis in NCI-H23 lung cancer cells... (C) AO EB staining ![file] For comparison: *[left]* Fig 1(E) from [Chen et al (2019)] .  AO EB staining for apoptosis . *[middle]* Figure 4 from [Li et al (2018)] .  AO EB staining showing induction of apoptosis in AMC-HN-8 cells upon treatment with Mukonal . *[right]* Fig 2C,D from [Du et al (2020)] .  DAPI staining of miR-NC and miR-143 mimics transfected CAMA-1 cells. ...  AO EB staining of miR-NC and miR-143 mimics transfected CAMA-1 cells . ![] , 
 Figure 4(D)  Effect of MAPK1 silencing on NCI-H23 invasion . ![file] For comparison: *[left]* Figure 7 from [Wei et al (2019)] .  Effect of Chrysoeriol on the invasion of the A549 cells as determined by Boyden chamber assay. The Figure shows that Chrysoeriol inhibited the tendency for invasion. *[right]* Figure 6 from [Li et al (2018)] .  Effect of Mukonal on the migration of the AMC-HN-8 cells as revealed by the Transwell assay. ![file] , 
 Figure 3B.  Suppression of lncRNA UCA triggers apoptosis in NCI-H23 lung cancer cells ...(B) annexin V PI staining . ![file] For comparison: *[left]* Fig 4 from [Zeng et al (2019)] .  Annexin V PI staining showing apoptotic CH157-MN cell percentage at indicated concentrations of chrysophanol. *[right]* Figure 1B from [Zhang et al (2018)] .  Metformin induces apoptosis in ovarian cancer cells. ... (B) Apoptosis assay for OVCAR-3 cells treated with metformin as determined by Annexin V PI double staining. ![] For added comparison, *[left]* Fig 5B from [Bi et al (2018)] .  Effect of indicated doses of genistein on apoptosis (A) DAPI staining (B) Estimation of apoptotic Mia-PaCa2 cell populations a indicated doses by annexin V PI using flow cytometry . *[right]* Figure 6 from [Zhang et al (2018b)] .  Annexin V PI showing apoptotic cell populations. .. The Figure shows that safranal triggered apoptosis at IC50 (20u03bcu039c). ![] , 
 Fig 3(D)  Comet assay . ![file] Comets can be periodic, but not **this** periodic. , 
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