Researchers at LMU have developed a human cell model that replicates key mechanisms of neurodegenerative diseases – with potential for novel therapies.
Neurodegenerative dementias present one of the greatest challenges for an aging society. The most common forms of dementia, such as Alzheimer’s disease and frontotemporal dementia, are characterized by pathological accumulation of the tau protein in the brain. These so-called tauopathies are not yet curable, partly due to a lack of suitable models for researching the disease mechanisms.
A research team led by Dominik Paquet from the Institute for Stroke and Dementia Research at LMU Munich has now achieved a crucial breakthrough: It has developed the first ever human cell model to realistically replicate the pathological processes.
Previous approaches had limitations. Animal models inadequately reflect the complex processes in the human brain, while neurons derived from stem cells mainly produce early forms of the tau protein usually found in very young brains. The variants that are decisive for the disease, which typically occur only in adult neurons, have been missing.
This is where the new study comes in. Using CRISPR/Cas9 genetic scissors, first author Angelika Dannert modified human neurons so that they form the adult tau isoform and carry disease-causing mutations.
Unlike earlier models, these cells independently developed disease features typical of Alzheimer’s disease and other tauopathies, including tau aggregates that closely resemble the deposits found in the brains of affected individuals, known as tangles, as well as signs of neuronal damage such as loss of synapses.
The researchers showed, moreover, that their new model is already opening up concrete prospects for drug development.
“A compound currently being tested in a clinical trial significantly reduced tau pathology. And we were also able to successfully test an imaging biomarker for the diagnosis of certain tauopathies,” Dannert said.
The model is an important advance from a scientific perspective, as it enables researchers for the first time to investigate pathological tau structures under realistic conditions.
“Our work closes an important gap between animal experiments and human disease, and the model provides a new platform for developing and testing urgently needed therapies against dementia,” Paquet said.
The researchers see their approach as a new tool for basic research and a promising foundation for developing therapies in a more targeted and efficient manner in the future.