Zileuton improves tauopathy in mice
Insufficient knowledge of mechanisms underlying dementia has hindered the development of effective therapies. A recent study provides new clues to the disease and may inform new treatments. The study, carried out by Temple University researchers, demonstrates that the drug zileuton, which is a specific leukotriene biosynthesis inhibitor, may be able to reverse tau pathological phenotype in Alzheimer's disease, the most common cause of dementia.
The study, titled 'Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway,' is published in Molecular Neurobiology.
Alzheimer's disease is associated with tau pathology (or tauopathy). Previous studies have unraveled that the leukotrienes pathway is upregulated in human tauopathy and manipulating the pathway influences the pathological phenotype of tau transgenic mice.
Leukotrienes, a group of pro-inflammatory molecules produced in leukocytes, have been shown to be often present in inflammatory tissues and to be generated by cells after an inflammatory stimulus. It has been long established that leukotrienes participate in the allergic reaction, and recent studies have suggested that they are also implicated in other disorders. Hence, blocking leukotriene action represents an approach to combating these disorders. One way to block leukotriene action is to use drugs to inhibit the enzyme 5-lipoxygenase that is required for the formation of leukotrienes. These drugs are known as leukotriene synthesis inhibitors, with zileuton as an example.
But, it remains unclear whether disrupting the biosynthesis of leukotrienes could have therapeutic effects after the pathological phenotype has fully developed.
To address this problem, three researchers from Temple University used aged tau transgenic mice. The mice were divided into two groups, one receiving zileuton and the other receiving vehicle. Results showed that zileuton-treated tau mice exhibited better memory and spatial learning compared with tau mice that had not received zileuton. In addition, zileuton-treated mice behaved in a similar fashion, in comparison to wild-type mice. Furthermore, zileuton treatment ameliorated synaptic integrity, neuroinflammation, and tau pathology.
According to senior author of the study Dr. Domenico Praticò, it's possible to intervene after disease is established and reverse tau-induced memory impairments. When the disease begins to develop, leukotrienes help protect neurons. But in the long term, leukotrienes cause damage.
To conclude, the study is the first to show that the leukotriene biosynthesis is functionally involved in the later stages of tauopathy. Thus, targeting the leukotriene biosynthesis may be a way to treat tauopathies such as Alzheimer's.