A groundbreaking study from the University of Cologne, published in the Journal of Alzheimer’s Disease and Cognitive, has identified certain forms of tau protein as key perpetrators of Alzheimer’s Disease, offering potential new targets for future treatments.
Using advanced stem cell and gene editing techniques, the international team demonstrates that out of six different variants of tau protein found in the human brain, 1N4R Tau, one particular form, is responsible for mediating toxic effects that lead to nerve damage.
Tau proteins have long been involved in Alzheimer’s disease, but this study could identify which specific variants promote cell damage and pave the way for more targeted treatments.
Detective work with brain cells
A research team led by Dr. Hans Sempel of the Institute for Human Genetics at the University of Cologne, employs equal techniques to investigate how different forms of tau behave in human neurons derived from stem cells.
Using CRISPR/CAS9 gene editing techniques, they first created neurons that were completely lacking tau protein. These “tau knockout” neurons showed mild developmental differences, but importantly, they were protected from the damage effects of amyloid beta oligomers (a protein mass characteristic of Alzheimer’s disease).
“This study represents important advances that will help us understand the mechanisms of Alzheimer’s disease. By identifying 1N4R tau as a key protein, we discovered potential new targets for future treatments,” says Dr. Sarah Buchholtz, the first author of the study.
Smoking gun
When researchers systematically reintroduced different tau variants into tau-depleted neurons, they made a prominent finding: only neurons containing the 1N4R tau mutant became vulnerable to amyloid beta-induced dysfunction. Other tau variants had minimal impact.
The team found that this 1N4R tau had significantly higher levels of certain types of phosphorylation (chemical modifications that affect protein function) at a site called serine 262. This phosphorylation appears to prevent proteins from properly adhering to cellular structures called microtubules.
The researchers demonstrated that the presence of the 1N4R tau mutant showed reduced activity in neurons following exposure to amyloid beta oligomers, similar to what happens in Alzheimer’s disease. Neurons lacking tau or containing other tau variants remained relatively protected.
Human model of human disease
This study demonstrates the importance of studying Alzheimer’s disease in human cell models. This is because the distribution and function of tau mutants differ between commonly used research animals such as humans and mice.
The researchers utilized human-induced pluripotent stem cells (IPSCs). It can be produced from the skin or blood cells and converted to neurons. This approach allowed them to investigate human-specific aspects of Alzheimer’s pathology that may not be captured in animal models.
Using live cell imaging techniques, teams can observe neuronal activity in real time and see how the presence of different tau variants affected the cell’s response to amyloid beta oligomers.
New targets for treatment
Current Alzheimer’s therapies focus on reducing amyloid beta levels or targeting a wide range of targets of any form of tau protein. This study suggests that a more selective approach targeting the 1N4R Tau variant is more effective and may have fewer side effects.
Identifying the 1N4R Tau variant as a key mediator of neurological dysfunction provides a more accurate target for future drug development efforts.
Interestingly, elimination of tau proteins shows that only mild changes in neural development and function are fully linked, suggesting that targeting approaches to specifically reduce 1N4R tau may be well tolerated.
The long road ahead
Despite this important advancement, significant additional research is needed to translate these findings into clinical treatments. The team noted that further research is needed to validate these results in appropriate animal models and develop specific therapeutic agents that selectively target the 1N4R tau variant.
For millions of people around the world who live with Alzheimer’s and their families, the study represents a promising step towards a more effective treatment for this devastating condition. By identifying specific protein variants that appear to promote neurological dysfunction, scientists have more accurate targets to develop interventions that may slow or stop disease progression.
This study is supported by Else-Kröner-Fresenius-Stiftung, the German Research Foundation, the Koeln Fortune Programme, and the Jürgen-Manchot-Stiftung, and additional support from the Alzheimer Forschung initiative.
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