Frontotemporal dementia (FTD) is a relatively rare form of dementia that primarily affects behavior and language, with damage occurring in the frontal and temporal lobes of the brain. Typically manifesting between the ages of 45 and 65 in individuals with a genetic predisposition, FTD is characterized by the accumulation of abnormal proteins in brain cells.
Driven by a desire to understand how specific mutations cause dysfunction in neural cells, researchers Henrik Ahlenius and Isaac Canals embarked on a journey of scientific exploration, focusing their investigations on FTD and a rare associated mutation in the gene CHMP2B.
From neurons to astrocytes - a closer look
Initially, their attention was directed towards neurons, the cells that allow for communication within the brain and between the brain and the body. "We wanted to understand the dysfunction in neurons and how this mutation triggers abnormal behavior among these cells," states Henrik Ahlenius, one of MultiPark's associated research group leaders and a principal investigator at Lund Stem Cell Center and Lund University.
To do this, the duo sought to create a model that accurately represented the genetic mutation found in patients with FTD. "Previous studies relied on animal models that utilized high levels of expression of the mutated protein to mimic FTD, but this does not represent the disease in humans," notes Isaac Canals, associate researcher at Lund Stem Cell Center and Lund University.
Unexpectedly, their initial findings posed more questions than answers, redirecting their focus toward another type of brain cell—astrocytes. Astrocytes are specialized brain cells that work in concert with neurons and other neural cells to ensure the proper functioning of the nervous system. Although prior research hinted at the possible involvement of astrocytes in FTD, their direct impact on neurons remained uncertain.
Introducing a New Model of FTD
Recognizing the significance of astrocytes and their potential role in FTD development, the research team set out to introduce the CHMP2B mutation into pluripotent stem cells using CRISPR technology.
Henrik Ahlenius explains, "By using reprogramming of human embryonic stem cells with a CRISPR-engineered CHMP2B mutation into neurons and astrocytes, we created a model that enables us to study astrocytes and neurons individually, as well as in a shared environment." This approach enables researchers to model diseases by introducing specific mutations into normal human cells, allowing them to study the impact of that specific mutation in brain cells in the lab.
Our findings highlight how dysfunctional astrocytes may trigger alterations within the neural network.
The results revealed both subtle neuronal dysfunction and more pronounced astrocytic dysfunction in the stem cell-derived model. "Our findings highlight how dysfunctional astrocytes may trigger alterations within the neural network and emphasize the interplay between astrocytes and neurons in neuronal dysfunction and the development of FTD," details Isaac Canals.
A New Frontier for Understanding Neurodegenerative Disorders
The study provides evidence of the involvement of astrocytes in FTD and the importance of studying the functionality of different types of neural cells and their interaction. As researchers delve deeper into the intricate interactions between neurons and astrocytes, this research paves the way for novel diagnostic methods, and therapeutic approaches, and opens avenues for the study of other neurodegenerative disorders and rare diseases.
"By better understanding the intricate relationship between astrocytes and neuronal dysfunction, we can develop more targeted therapies that address the underlying causes of these diseases," concludes Isaac Canals.
Henrik Ahlenius adds, "We hope that our findings will inspire further research and collaboration in this field, ultimately leading to effective treatments for patients."