Alzheimer’s Achilles Heels: Scientists point out key protein mutations that drive brain cell damage

According to a groundbreaking study published in the journal University of Alzheimer’s & Dementia, a specific form of tau protein has been identified as the key culprit for Alzheimer’s disease, providing potential new targets for future treatment.

Using advanced stem cell technology and gene editing techniques, the international team showed that among the six different variants of tau protein found in the human brain, a special form (a type called 1n4r tau) was shown to be primarily responsible for mediating the toxic effects that lead to neuronal damage.

Although long-standing related to Alzheimer’s disease, the study points out which specific variants may drive cell damage, which has the potential to open up new avenues for more targeted therapies.

Detective work in brain cells

The research team was led by Dr. Hans Zempel of the Institute of Human Genetics at the University of Cologne, who used exquisite techniques to study the performance of different forms of TAU in human neurons in stem cells.

They used CRISPR/CAS9 gene editing technology to create neurons that were completely lacking in Tau protein. These “tau knockout” neurons show mild developmental differences, but are crucially protected from the destruction of amyloid beta oligomers, which are characterized by Alzheimer’s disease.

“This study represents a significant advancement in helping us understand the mechanisms of Alzheimer’s disease. By identifying 1N4R TAU as a key protein, we have identified potential new goals for future treatments,” said Dr. Sarah Buchholz, the first author of the study.

Smoking gun

When the researchers systematically reintroduced tau-deleted neurons, they made a surprising discovery: Only neurons containing 1N4R TAU variants are susceptible to amyloid beta-induced dysfunction. The impact of other tau variants is minimal.

The team found that the 1N4R TAU was significantly higher in a specific type of phosphorylation level (a chemical modification that affects protein function) at a site called serine 262. This phosphorylation seems to prevent the protein from properly connecting to a cellular structure called a microtubule, but rather allows it to accumulate in the region of its neurons.

The researchers demonstrated that when the 1N4R TAU variant is present, neurons have reduced activity after exposure to amyloid beta oligomers, similar to what happens in Alzheimer’s disease. Neurons lacking TAU or containing other TAU variants are still relatively protected.

Human models of human disease

This study shows the importance of studying Alzheimer’s disease in human cell models because of the different distribution and function of tau variants in humans and mice (such as mice).

The researchers used human-induced pluripotent stem cells (IPSCs)—cells that can be produced from skin or blood cells that are then converted into neurons. This approach allows them to study human-specific aspects of Alzheimer’s disease pathology that may not be captured in animal models.

Using live cell imaging technology, the team can observe neuronal activity in real time to see how the presence of different TAU ​​variants affects the cell’s response to amyloid beta oligomers.

A new treatment goal

Current Alzheimer’s treatment focuses on reducing amyloid beta levels or targeting all forms of tau proteins widely. This study suggests that a more selective approach to the 1N4R TAU variant may be more effective and may cause fewer side effects.

Identifying the 1N4R TAU variant as a key mediator of neuronal dysfunction provides a more precise target for future drug development efforts.

Interestingly, this study showed that elimination of tau protein completely leads to slight changes in neuronal development and function, suggesting that targeted targeting methods for reducing 1N4R tau may be well tolerated.

The long road ahead

Despite this important advance, translating these findings into clinical treatment will require a lot of additional research. The team notes that further research is needed to validate these results in appropriate animal models and to develop specific therapies that can selectively target the 1N4R TAU variant.

For millions of people living around the world in Alzheimer’s disease and their families, the study represents a promising step towards a more effective treatment of this devastating disease. By identifying specific protein variants that appear to drive neuronal dysfunction, scientists now have more precise targets for developing interventions that may slow or stop disease progression.

This study was supported by Else-Kröner-Fresenius-Stiftung, the German Research Foundation, the Koeln Fortune Program and Jürgen-Manchot-Stiftung, and was additionally supported by the Alzheimer’s Foxson Program published for open access.