Trinity crew uncovers mutations connected with early onset dementia

Overview

• Post By : Kumar Jeetendra


• Source: Trinity College Dublin


• Date: 22 Dec,2020

Researchers at Trinity College Dublin today announced a significant advance in our knowledge of an early onset form of dementia which may also advance our understanding of conditions such as Alzheimer’s disease.

Adult onset Leukoencephalopathy with axonal Spheroids and Pigmented glia (ALSP) is an ultra-rare condition characterized by mutations in a gene named Colony stimulating factor-1 receptor (CSF1R). The condition manifests initially with psychiatric and behavioral changes in patients followed by a rapid progression of dementia in the third or fourth decade of life. While the condition is extremely rare, for affected families it may represent a devastating diagnosis.

As the condition involves the degeneration of white matter in the brain, scientists previously thought that immune cells within the brain termed microglia were the primary culprits in driving pathology observed in this condition.

However, the Trinity team, working with individual samples in addition to pre-clinical models, managed to show that dysfunctional circulating white blood cells were the primary driver of neurodegeneration.

“This was fundamentally a translational research project, where information obtained from patient samples critically informed the management of our pre-clinical studies. Our findings have shed light on a novel mechanism of neurodegeneration that may ultimately teach us more about common types of dementia,” said Dr Matthew Campbell, Associate Professor at Trinity.

The most exciting aspect of our study is that we have now honed in on a novel pathway that to date has not been explored in great detail. Additionally, our data suggest that modifying white blood cell function may be therapeutically relevant for progressive neurodegenerative conditions.”

Dr. Conor Delaney, Irish Research Council scholar, First author, Postdoctoral research fellow

Importantly, the work has identified that a disruption in CSF1R function in patients, in addition to in pre-clinical models, induces damage to the so-called adrenal barrier (BBB). This damage can subsequently change the integrity of capillaries in the brain, causing them to flow and provoke the deterioration of the brain. Intriguingly, dysfunctional white blood cells seem to be the main driver of the BBB breakdown.

Unfortunately, there are currently no approved therapies for conditions such as Alzheimer’s disease, which is in part because of the lack of a robust understanding of the early initiators of disease. If we can better understand what the early hallmarks of Alzheimer’s are, we may be able to develop novel forms of therapy that target these recently discovered mechanistic pathways.

While shedding light on an often-neglected rare disorder, the findings may pave the way for a targeted therapeutic approach for different kinds of dementia.

Commenting on the clinical significance of the findings, Colin Doherty, Professor of Epilepsy at Trinity, stated:”It is absolutely critical that we focus our research endeavors on identifying the root cause of climatic conditions. Studies such as these will pave the way for better clinical management of our patients and hopefully new medicines to treat the problem.”