A novel mutation in rare dementia informs about Alzheimer’s therapy

Mutations in the CSF-1R gene have been linked to a rare form of dementia called leukoencephalopathy, which may help develop therapy for Alzheimer’s disease.

These findings are reported in the article, “Decreased CSF-1R signaling triggers cerebrovascular pathology,” published in EMBO Molecular Medicine.

Commenting on the clinical significance of the findings, Colin Doherty, Ph.D. Med., FRCPI, FFESM, a professor of epilepsy at Trinity College, said: “It is absolutely crucial that we focus our research efforts on identifying the root cause of neurodegenerative conditions. Such studies will pave the way for better clinical treatment of our patients and hopefully new drugs to treat the condition. “

Alzheimer’s disease is the fourth leading cause of death in the world. Currently, about 36 million people suffer from Alzheimer’s disease or related dementias globally, and there are no approved drugs that prevent the disease from progressing. Pathologies related to blood vessels in the brain occur in about 80% of patients with Alzheimer’s disease and are poorly understood.

“What we wanted to do in our study was to examine a very rare form of brain disease called leukoencephalopathy with very similar characteristics to Alzheimer’s disease. We have defined the genetic cause of this condition “, said Dr. Mathew Campbell, associate professor at Trinity and senior author of the study.

Immunohistochemistry of a patient's leukoencephalopathy
Glial fibrillar acidic protein (GFAP) and staining of Claudin-5 affected cells.

“We discovered two new mutations in a gene called the colony-stimulating factor-1 receptor or CSF-1R. These mutations have led to a loss of the function of the white blood cells circulating in your body. And now we have linked this loss of function to damage to the blood vessels in the brain that leads to dementia, ”said Dr. Conor Delaney, a postdoctoral researcher.

Adult leukoencephalopathy is characterized by swollen axons, pigmented glia, and accumulation of amyloid plaques on the walls of arteries in the brain. The condition is initially manifested by psychiatric and behavioral changes in patients accompanied by rapid progression of dementia in the third or fourth decade of life. Although the condition is very rare, it is devastating for affected families.

Scientists previously believed that leukoencephalopathy was caused by immune cells in the brain called microglia, because the pathology of the disease involves the degeneration of white matter in the brain.

The present study identified two families with different mutations located in the enzymatically active region of the CSF-1R gene. The protein product of this gene acts as a receptor for two related ligands: colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). The function of CSF-1R is crucial for the activation of microglia and macrophages – white blood cells that swallow and destroy aberrant material such as bacteria or cell debris.

The study showed that loss of CSF-1R signaling disrupts the blood-brain barrier and reduces the ability of peripheral macrophages to swallow material without affecting microglia function. When CSF-1R function is compromised, macrophages cannot effectively reset amyloid plaques.

Brain immunohistochemistry
Amyloid-beta (green) and Claudin-5 (red) staining in the brain of a patient with leukoencephalopathy.

“This was basically a translational research project, where data obtained from patient samples critically informed the direction of our preclinical studies. Our findings shed light on a new mechanism of neurodegeneration that could eventually teach us more about common forms of dementia, ”Campbell said.

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

This suggests that regulation of the integrity of the blood-brain barrier and recruitment of macrophages into the brain are therapeutically relevant for leukoencephalopathy and other Alzheimer’s dementias.

“We have identified potential therapeutic targets that could benefit both this rare disease, leukoencephalopathy, but also much more common forms of dementia like Alzheimer’s disease,” Campbell said.