Research into an ultra-rare type of early-onset dementia has uncovered a novel genetic mutation that results in dysfunctional white blood cells and a breakdown of the blood-brain barrier. The study suggests this newly discovered mechanism of neurodegeneration may play a role in more common types of dementia, such as Alzheimer’s disease.
Led by scientists from Trinity College London the new research set out to investigate the mechanisms underpinning a very rare neurodegenerative disease called adult onset Leukoencephalopathy with axonal Spheroids and Pigmented glia (ALSP). The clinical symptoms of this hereditary condition resemble Alzheimer’s disease but it appears at a much younger age (early 40s) and causes rapid neurodegeneration over a period of five to 10 years.
ALSP is known to be caused by mutations in the CSF1R gene. A common hypothesis is CSF1R mutations lead to dysfunctional behavior from microglia, a type of immune cell in the brain. But a new hypothesis is presented in this study suggests an entirely different mechanism may underpin the neurodegeneration seen in ALSP.
Using post-mortem brain tissue samples and pre-clinical models the team of Trinity College researchers discovered certain CSF1R mutations result in abnormal activity in macrophages, a common type of white blood cell. These dysfunctional white blood cells were found to damage the blood-brain barrier and it is this chain of events that may be driving the progressive neurodegeneration.
“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,” says first author on the new study, Conor Delaney. “Additionally, our data suggest that modifying white blood cell function may be therapeutically relevant for progressive neurodegenerative conditions.”
Although ALSP is an incredibly rare disease, it shares many pathological characteristics with Alzheimer’s. So the researchers suggest this particular finding, focusing on white blood cell dysfunction driving blood-brain barrier damage, may be transferable to Alzheimer’s-related dementias.
Interestingly, this is not the first hypothesis to suggest common neurodegeneration may be triggered by damage to the blood-brain barrier. A growing body of research has begun to convincingly present strong links between the earliest stages of cognitive decline and the blood-brain barrier breaking down. In fact, a compelling 2018 review article went as far as suggesting a dysfunctional blood-brain barrier could play a part in the earliest stages of many neurological disorders, from Alzheimer’s and Parkinson’s to ALS and multiple sclerosis.
Colin Doherty, another author on the new study, suggests studying these rare, rapidly progressing forms of neurodegenerative disease allows for unique insights into the mechanisms that more slowly play out in common forms of dementia, and this newly discovered mechanism opens the door for entirely novel research pathways.
“It is absolutely critical that we focus our research endeavors on identifying the underlying cause of neurodegenerative conditions,” says Doherty. “Studies like these will pave the way for better clinical management of our patients and hopefully new medicines to treat the condition.”
The new study was published in the journal EMBO Molecular Medicine and the study is discussed in the video below.
Scientists discover mutations associated with early onset dementia
Source: Trinity College Dublin
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