Scientists have discovered an enzyme that may trigger Alzheimer’s. Blocking it could reduce toxic tau buildup.
Alzheimer’s disease is recognized as one of the most significant global health challenges. Despite millions of individuals being diagnosed with the condition annually, effective treatment options remain elusive, primarily due to the incomplete understanding of its underlying causes.
Recent research conducted on mice has provided a step forward in unraveling the mechanisms that may trigger the disease. A specific enzyme has been identified as potentially responsible for one of the hallmark characteristics of Alzheimer’s.
A defining feature of Alzheimer’s disease is the abnormal accumulation of a protein known as tau. In a healthy brain, tau plays a crucial role in supporting and stabilizing brain cells, or neurons. This stabilization maintains cellular structure and facilitates the transport of essential substances within neurons, ensuring optimal functionality.
However, in cases of Alzheimer’s, tau behaves abnormally. Rather than fulfilling its normal role, it accumulates inside neurons, forming twisted clumps referred to as neurofibrillary tangles. These tangles are known to disrupt communication between neurons, which is critical for memory, thinking, and behavior. Such disruptions can lead to significant damage in the affected regions of the brain.
Although the involvement of tau in Alzheimer’s has been understood for decades, the precise reasons behind its misfolding into toxic, sticky tangles remain unclear. The latest study, published in *Nature Neuroscience*, offers promising new insights into the process by which tau becomes toxic, as observed in mice.
“Understanding the mechanisms behind tau’s transformation is a critical step toward developing targeted therapies for Alzheimer’s disease,” the researchers noted.
This discovery highlights the importance of continued research into the molecular processes underlying Alzheimer’s, offering hope for future advancements in treatment and prevention.
Toxic Tau
To model Alzheimer’s disease, a team of US-based scientists utilized mice genetically modified to exhibit a buildup of tau in their brains. It was discovered that a specific enzyme might be responsible for transforming healthy tau into its toxic form, which accumulates in the brain.
Enzymes, typically known for their beneficial roles in the body, facilitate reactions to occur more quickly and efficiently. However, this study revealed that the enzyme tyrosine kinase 2 (TYK2), which is central to immune system function, attaches a specific marker to tau. This marker appears to hinder the brain’s ability to clear away excess tau effectively. In both mouse models and human cell cultures, the presence of this enzyme led to the accumulation and toxicity of tau.
Through genetic techniques, the scientists inhibited TYK2 in the Alzheimer’s-afflicted mice. This intervention resulted in a reduction of total tau levels in the brain, including the harmful, disease-causing tau marked by the enzyme. Additionally, signs of neuronal recovery were observed, suggesting that blocking TYK2 could mitigate the buildup of toxic tau and the damage it causes in conditions like Alzheimer’s. This discovery could pave the way for novel drug development targeting toxic tau through previously unexplored mechanisms.
The potential of lowering or blocking TYK2 as a treatment for Alzheimer’s is particularly promising, given that TYK2 inhibitor drugs have already undergone testing in humans for various conditions, including autoimmune diseases such as psoriatic arthritis and inflammatory bowel disease.
However, further research is necessary to determine whether TYK2 inhibitors can effectively cross the blood-brain barrier. Since tau is located within brain cells, its removal poses significant challenges. If these drugs cannot reach the brain, their ability to reduce tau levels and impact Alzheimer’s disease in humans will be limited.
“The ability to target and reduce toxic tau buildup represents a significant step forward in the fight against Alzheimer’s,” the researchers noted.
This breakthrough underscores the importance of continued exploration into innovative therapeutic strategies, offering hope for advancements in addressing Alzheimer’s and related neurodegenerative conditions.
Alzheimer’s Treatments
The need for new treatment options for Alzheimer’s disease is urgent. Although two therapies, donanemab and lecanemab, have recently been approved in the UK, their high cost limits widespread availability on the NHS, and they are associated with significant side effects. Many argue that the drawbacks of these treatments may outweigh their potential benefits.
These therapies primarily focus on removing amyloid plaques, another protein implicated in Alzheimer’s. However, targeting tau, the protein central to this new research, could represent a transformative approach in the search for more effective treatments.
It is important to note that this research is still in its early, pre-clinical stages. While mouse models are invaluable for understanding disease mechanisms, findings from such studies do not always directly translate to humans. Further research is required to determine whether this technique similarly reduces tau levels in the human brain, whether harmful side effects are associated with it, and whether blocking TYK2 to clear toxic tau leads to improvements in Alzheimer’s symptoms, such as memory loss.
Targeting TYK2 to reduce toxic tau in the brain holds promise as a potential new strategy for treating Alzheimer’s. The next steps will involve exploring whether these findings can be replicated in human studies.
“The potential to target tau represents a significant shift in Alzheimer’s research, offering hope for more effective and accessible treatments,” the researchers emphasized.
This development highlights the importance of continued innovation in Alzheimer’s research, with the goal of addressing the urgent need for safer, more effective therapies.
https://www.nature.com/articles/s41593-024-01777-2
Abstract
Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.