Scientists discover genetic mutations associated with early dementia

This image shows glial fibrillar acid protein (GFAP) and Claudin-5 staining of an affected cell. Credit: Trinity College Dublin

Scientists at Trinity College Dublin today announced a major breakthrough in our understanding of an early onset of dementia that undermines our understanding of conditions such as Alzheimer’s disease.

Adult onset of leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an extremely rare condition characterized by mutations in a gene called Colony Stimulating Factor-1 Receptor (CSF1R). The condition initially manifests with psychiatric and behavioral changes in patients, followed by a rapid progression of dementia in the third or fourth decade of life. Although the condition is very rare, it can be a devastating diagnosis for affected families.

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

However, the Trinity team, who worked with patient samples as well as pre-clinical models, were able to show that dysfunctional circulating white blood cells were the major driver of neurodegeneration.

‘It was fundamentally a translation research project, where data obtained from patient samples critically informed the direction of our preclinical studies. Our findings have shed light on a new mechanism of neurodegeneration that could eventually teach us more about common forms of dementia, ‘says Dr Matthew Campbell, associate professor at Trinity.

Importantly, the work identified that a disruption in CSF1R function in patients, as well as in preclinical models, causes damage to the so-called blood-brain barrier (BBB). This damage can alter the integrity of capillaries in the brain, causing it to leak and cause the brain to deteriorate. Strikingly, dysfunctional white blood cells are the major driver of this BBB breakdown.

Relevance to other dementias

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

Amyloid beta and Claudin-5

Amyloid beta and Claudin-5 staining in the brain of a patient with ALSP. Credit: Trinity College Dublin

Dr. Conor Delaney, Irish Research Council student, postdoctoral fellow and first author of the study, added: ‘The most exciting aspect of our study is that we have now honed a new path that has not been much explored to date. details. In addition, our data suggest that altering the function of white blood cells may be therapeutically relevant to progressive neurodegenerative conditions. ”

A multidisciplinary team of geneticists, immunologists, neurologists and neuropathologists from Trinity, the Royal College of Surgeons Ireland (RCSI), University College Cork (UCC), Sligo General Hospital and the University of Ghent undertook the study.

While shedding light on a rare disease that is often neglected, the findings may pave the way for an effective therapeutic approach to other forms of dementia.

Colin Doherty, professor of epilepsy in trinity, said of the clinical significance of the findings: ‘It is absolutely critical that we try to focus our research on identifying the underlying cause of neurodegenerative conditions. Studies like these will pave the way for better clinical management of our patients and hopefully new medicines to treat the condition. ”

Reference: December 22, 2020, EMBO Molecular Medicine.
DOI: 10.15252 / emmm.202012889

The research, published in the International Journal this week, EMBO Molecular Medicine, was supported by the Irish Research Council (IRC), Science Foundation Ireland (SFI) – Future Neuro Center, the St James’s Hospital Foundation and the legacy of Ellen Mayston Bates in the Trinity Foundation.

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