For the first time in an animal model, researchers at the Lewis Katz School of Medicine at Temple University showed that the tau pathology that accompanies Alzheimer’s disease can be reversed using the asthma drug zileuton [1].

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.

The old culprits

Tauopathies are a group of chronic, neurodegenerative diseases characterized by the accumulation of insoluble tau proteins in certain types of neurons. In the specific case of Alzheimer’s disease, the prevailing hypothesis about its etiology is that an accumulation of amyloid-beta and tau proteins leads to the formation of neurofibrillary tangles that strangle synapses—the connections between brain cells—disrupting communication between neurons and resulting in a decline in memory and learning abilities along with general cognitive impairment. Several drugs have been developed that target these protein aggregates, but the human version of the disease still has no cure.

A new suspect joins in

A new study led by Dr. Praticò—who holds the Scott Richards North Star Foundation Chair for Alzheimer’s Research at Temple University—made an interesting discovery; namely that leukotrienes are involved in the development of tau pathology.







Leukotrienes are inflammatory mediators produced by leukocytes via the arachidonate 5-lipoxygenase enzyme. They use lipid signaling for sending information to either the cell producing them (autocrine signaling), or to nearby cells (paracrine signaling) to mediate immune responses. Leukotrienes are already known for their involvement in asthma, and their production can be inhibited indirectly by inhibiting the action of arachidonate 5-lipoxygenase, which is exactly what the drug zileuton does.

In previous studies [2-4], Dr. Praticò’s team found out that leukotrienes play a role in the later stages of tauopathy-induced dementia. In the earlier stages of the disease, the molecules intervene in an attempt to protect neurons, but, in its later stages, they end up causing damage.

In the same studies, the researchers showed that inhibiting the 5-lipoxygenase enzyme in transgenic mice significantly ameliorated or retarded the insurgence of pathology, but in these cases, action was taken only early on in the life of the mice, well before tauopathy set in; in their newer study, the researchers set out to establish whether blocking the action of leukotrienes would yield any benefits in mice already affected by tau-induced lesions.

The experiment

To test their idea, the scientists made once more use of transgenic mice engineered to develop tau pathology as they aged. The animals exhibited both the physical signs of the disease—that is, the accumulation of tau protein and tangles—and the overall cognitive and spatial learning impairment and memory loss. Some of the mice were randomly chosen to be treated with zileuton at one year of age—well into middle age by mouse standards—whereas others acted as controls.







After a 16-week period, the mice were given maze tests in order to assess their memory and learning ability. The test group mice that had been treated with zileuton were significantly better at the tests compared to the control group, which suggests that memory impairment had been reversed.

To find out why this had happened, the researchers looked at the leukotriene levels in both groups of mice and found that the mice given zileuton showed 90 percent lower levels of leukotrienes compared to the control mice. The levels of tau protein were an impressive 50 percent lower in treated animals. Finally, in the treated mice, the synapses were indistinguishable from ordinary mice without the disease, while the control mice had severe synaptic deterioration.

The researchers report that inflammation was gone from the tau model mice treated with the drug, as the therapy blocked the inflammation process in the brain and allowed the damage caused by tau to be repaired.

Conclusion

This is an interesting result and demonstrates that the damage caused by tau is not a one-way process. Zileuton is already approved by the FDA for the treatment of asthma, so it could potentially be clinically applied to treat human patients suffering from Alzheimer’s and other tauopathies.







Literature

[1] Giannopoulos, P. F., Chiu, J., Praticò, D. (2018). Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway. Molecular Neurobiology, 1-10.

[2] Giannopoulos, P. F., Chu, J., Sperow, M., Li, J. G., Yu, W. H., Kirby, L. G., … & Praticò, D. (2015). Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy. Biological psychiatry, 78(10), 693-701.

[3] Vagnozzi, A. N., Giannopoulos, P. F., & Praticò, D. (2017). The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. Translational psychiatry, 7(12), 1288.

[4] Giannopoulos, P. F., & Praticò, D. (2017). Overexpression of 5-Lipoxygenase Worsens the Phenotype of a Mouse Model of Tauopathy. Molecular neurobiology, 1-11.





