Will kinase inhibitors help with Alzheimer's disease?

Kinase inhibitors reduce tau phosphorylation in mouse models of Alzheimer's disease

LifeSciencesToday based on materials from UC Santa Barbara:
Alzheimer's Disease Mouse Models From UCSB's Neuroscience Research Institute Point To A Potential Therapeutic ApproachBased on the results of their own study published eight years ago in the journal Chemistry & Biology, Professor of neurology Kenneth Kosik from the University of California at Santa Barbara (California University - Santa Barbara) and his group have found a new potential target for the fight against Alzheimer's disease and other neurodegenerative diseases.

The results of their recent experiments on two different mouse models of Alzheimer's disease are published online as an "Article of the Week" in The Journal of Biological Chemistry: Zhang et al., Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models; Ahn et al., Defining Cdk5 Ligand Chemical Space with Small Molecule Inhibitors of Tau Phosphorylation.

Professor Kosik and his colleagues focused their attention on tau protein, a protein commonly present in the brain capable of forming neurofibrillary tangles, which, along with beta-amyloid plaques, are a characteristic feature of Alzheimer's disease. Pathological tau protein actively binds phosphate groups – it is hyperphosphorylated. Clusters of hyperphosphorylated tau are also called paired spiral filaments.

Neurofibrillary tangles in pyramidal neurons (colored bright red) –
one of the signs of Alzheimer's disease (photo: Israel Hernandez, UCSB)

There are no methods of influencing the process of hyperphosphorylation of tau, one of the main causes of Alzheimer's disease. The possibilities of modern medicine are limited by prescribing drugs that increase the concentration of neurotransmitters that improve interneuronal signaling.

However, the results of Professor Kosik's latest study suggest that it is possible to influence the phosphorylation process with low molecular weight compounds of the diaminothiazoles class, acting as inhibitors of kinase enzymes that phosphorylate tau. The scientists studied the toxicity and immunoreactivity of several diaminothiazoles targeted by two key kinases – CDK5/p25 and GSK3beta – in two mouse models of Alzheimer's disease and found that at therapeutic doses, these compounds effectively inhibit enzymes with virtually no toxic effects.

Treatment with LDN-193594 lead compound had a significant effect on the loss of nerve cells accompanying increased CDK5 activity. Diaminothiazole kinase inhibitors not only reduced tau phosphorylation, but also had a neuroprotective effect in vivo. In addition to reducing the number of paired spiral filaments in the brains of mice, they, under certain conditions, restored the ability to learn and memory.

According to the authors, the fact that diaminothiazoles reduce the phosphorylation of tau strongly suggests that treatment with low-molecular kinase inhibitors can slow down the development of tau pathology. "Given the contribution of both CDK5 and GSK3beta to tau phosphorylation," says Professor Kosik, "targeting of both kinases may be required for effective treatment of taupathies."

"As a first step, we have shown that two of these compounds successfully clear the brain of tangles of tau in a mouse model, but someday inhibitors of these kinases will serve to alleviate the symptoms of Alzheimer's disease in patients," adds Madison Cornwell, one of the study participants.

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