Potential therapeutic targets for leukoencephalopathy and dementia like Alzheimer’s disease

A rare type of dementia called leukoencephalopathy has been related to mutations in the CSF-1R gene, which may help develop therapeutics for Alzheimer's disease.

Colin Doherty, MD, FRCPI, FFESM, professor of epilepsy, Trinity College, reflecting on the clinical relevance of the results, said that: "It is absolutely critical that we focus our research efforts on identifying the underlying cause of neurodegenerative conditions." Studies such as these will pave the way for our patients to have improved health management and potentially new drugs to treat the disease.

This research was reported in the article, “Attenuated CSF-1R signaling drives cerebrovascular pathology,” published in EMBO Molecular Medicine.

The fourth leading cause of death globally is Alzheimer's disease. Currently, nearly 36 million people worldwide suffer from Alzheimer's disease or associated dementia and no licenced medications are available to prevent the worsening of the disease. Blood vessel-related pathologies in the brain arise in about 80% of Alzheimer's disease patients and are poorly understood.

In their research, they tried to do was to investigate a very unusual type of brain disease called leukoencephalopathy with symptoms very similar to Alzheimer's disease. Mathew Campbell, PhD, associate professor at Trinity and senior author of the research, said that we have identified the genetic cause of this disease.

"In a gene called colony stimulating factor-1 receptor or CSF-1R, we have discovered two new mutations. These defects in the white blood cells that circulate in the body have contributed to a loss of function. And now we've related this loss of function to damage to the brain's blood vessels that leads to dementia,' said Conor Delaney, PhD, a postdoctoral fellow in science.

Swollen axons, pigmented glia, and the building up of amyloid plaques on the walls of the arteries in the brain define adult-onset leukoencephalopathy. The disease initially manifests with psychiatric and behavioural changes in patients, accompanied in the third or fourth decade of life by a gradual development of dementia. Although the disease is very unusual, for affected families it is devastating.

Scientists previously assumed that immune cells within the brain called microglia caused leukoencephalopathy because the pathology of the disease involves degeneration of the brain's white matter.

The current study identified two families located in the enzymatically active region of the CSF-1R gene with different mutations. This gene's protein product serves as a receptor for two associated ligands: colony stimulating factor-1 (CSF-1) and interleukin-344 (IL-34). For the activation of microglia and macrophages, white blood cells that engulf and kill aberrant material such as bacteria or cellular debris, the CSF-1R role is important.

The study showed that CSF-1R signalling loss disrupts the blood brain barrier and reduces the ability of peripheral macrophages to swallow material without affecting microglia activity. Macrophages will not effectively zero in  amyloid plaques when the function of CSF-1R is impaired.

In essence, this was a translational research project, where data collected from patient samples critically influenced the course of the preclinical studies. Our findings have shed light on a novel neurodegenerative mechanism that can potentially tell us all about common types of dementia,” Campbell said.

The authors also showed that the intercellular interactions of the blood brain barrier and the loss of CSF-1R function in patients and preclinical model animals were reshaped by molecular crosstalk between cells lining the blood vessels (endothelial cells) and microglial cells, destroying the blood brain barrier.

This indicates that for leukoencephalopathy and other Alzheimer's-like dementias, regulating the integrity of the blood brain barrier and the recruitment of macrophages to the brain are therapeutically important.

in this work Potential therapeutic targets have been identified that could benefit both this rare leukoencephalopathy disease and much more common forms of dementia such as Alzheimer's disease.