AD Study Explores How Tau Protein Turns Toxic

graphic illustration of neurons damaged by alzheimers disease

A key marker of Alzheimer’s disease (AD) is the accumulation of tau, a protein that functions as a neuronal support mechanism in a healthy brain. In individuals with AD, this generally supportive protein begins to behave abnormally in the brain. Over time, the protein builds up and forms clumps called neurofibrillary tangles, which can disrupt communication between neurons and negatively impact memory, thinking, and behavior, exacerbating the symptoms of AD. Scientists are still unsure exactly how healthy tau begins to form these toxic tangles, but a new study, published in Nature Neuroscience, could explain the transformation. The study involved the PS19 mouse model, a mouse that is transgenic for the tau P301S mutation, as well as a PS19 mouse model with a knockdown of tyrosine kinase 2 (TYK2), a potentially harmful enzyme.

Testing the Effects of TYK2 on Abnormal Tau

To mimic Alzheimer’s disease, the research team worked with mice that had been genetically altered to accumulate tau in their brains. As mentioned above, the researchers used the PS19 mouse model, which is transgenic for the tau P301S mutation.

By evaluating these mice, the research team discovered that a specific enzyme may be responsible for turning healthy tau into toxic, tangled tau. The enzyme tyrosine kinase 2 (TYK2), known to play a central role in the immune system, was found to add a special tag to the protein, which appears to make it difficult for the brain to clear away unnecessary tau. The enzyme was found to have a similar effect in both mouse models and human cell cultures, which could prove promising for future treatment interventions.

To explore potential interventions, the researchers worked with a second PS19 mouse model. This model also featured a knockdown of TYK2, implemented by intracerebroventricular injection of an AAV8 harboring TYK2 shRNA. TYK2 knockdown reduced the overall amount of tau in the brain, including the toxic tau. This suggests that blocking TYK2 could be a route to reduce harmful tau buildup.

Evaluating the Efficacy of TYK2 Against Tau

The findings of this study are undoubtedly positive, especially given the fact that some TYK2 inhibitor drugs have already been tested in humans. These drugs have been tested for a number of inflammatory conditions, including psoriatic arthritis and inflammatory bowel disease. However, researchers need to determine if TYK2 inhibitors can pass the blood-brain barrier to impact tau within brain cells. If the inhibitors are unable to pass the barrier, the drugs will not be effective against Alzheimer’s disease and similar neurodegenerative illnesses.

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While this research is promising, its findings should be considered with the utmost care. First, the research is preclinical and in its very early stages. Additionally, mouse models don’t always translate directly to humans. Ultimately, more research will be necessary to understand whether TYK2 inhibitors could impact pathological tau levels in the human brain — and whether that impact could translate to a new, effective treatment for Alzheimer’s disease.

To study Alzheimer’s disease-related tau pathology, Scantox Neuro offers preclinical research using the PS19 mouse model, which is the model utilized in the study presented above. We offer other related mouse models as well, including the hTau mouse model, which was designed to express human tau while murine tau is knocked out, and the TMHT mouse model, which expresses the longest human tau isoform Tau441 (2N4R) with V337M and R406W mutation. Mice can be evaluated in vivo for disease-specific behavioral deficits such as learning and memory. Ex vivo, tissue can be analyzed for disease-specific pathologies using histological and biochemical approaches. Additionally, in vitro models to study tau pathologies are available. All models can be analyzed for tau aggregation, phosphorylation, inflammation, synaptic alterations, and more.

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