New Mutations Discovered In Rare Dementia

Raj @ Mission — Sat, 26 Dec 2020 05:16:47 +0000

Source – https://worldhealth.net/

Current estimates are that around 36 million people suffer from Alzheimer’s disease or related dementias, and there are no approved medications to prevent the progression of this mind wasting debilitating disease which is the fourth leading cause of death around the globe.

Pathologies related to blood vessels in the brain occur in around 80% of those diagnosed with Alzheimer’s disease, and the underlying mechanisms that lead to perivascular pathology and accompanying BBB disruption are poorly understood. Recent research published in EMBO Molecular Medicine has identified mutations in the gene CSF-1R that have been linked to a rare form of dementia called leukoencephalopathy, findings may help develop therapeutics for AD.

Commenting on the clinical significance of the findings, Colin Doherty, MD, FRCPI, FFESM, professor of epilepsy, Trinity College, said: “It is absolutely critical that we focus our research endeavors 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.”

“What we sought 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’ve defined the genetic cause of this condition,” said Mathew Campbell, Ph.D., associate professor at Trinity and senior author on the study.

“We’ve discovered two new mutations in a gene called colony-stimulating factor-1 receptor or CSF-1R. These mutations have led to a loss of function in the white blood cells that circulate throughout your body. And we’ve now tied this loss of function to damage at the blood vessels of the brain which leads to dementia,” said Conor Delaney, Ph.D., postdoctoral research fellow.

Adult-onset of leukoencephalopathy is characterized by swollen axons, pigmented glia, and by the building up of amyloid plaques on the walls of the arteries in the brain. This condition is very rare but devastating to the affected families with the disease initially manifesting with psychiatric and behavioral changes which are followed by a rapid progression of dementia in the third to fourth decade of life.

Leukoencephalopathy was believed to be caused by microglia immune cells within the brain due to the disease pathology involving degeneration of brain white matter. This study identified two families with different mutations located in the enzymatically active region of the CFS-1R gene. The protein product of this gene acts as the receptor for 2 related ligands: CSF-1 and IL-34. CSF-1R function is important to the activity of microglia and white blood cell macrophages that engulf and destroy aberrant materials like cellular debris and bacteria.

In this study the loss of CSF-1R signaling was shown to disrupt the blood-brain barrier and decrease the capacity of peripheral macrophages to engulf materials without affecting the function of microglia; when this function is compromised macrophages are not able to zero in on amyloid plaques effectively.

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

Molecular crosstalk between endothelial cells lining blood vessels and microglial cells remodeling the intercellular interactions of the blood-brain barrier and the loss of CSF-1R function was also shown to damage the BBB in preclinical model animals and patients.

Findings suggest that regulating the integrity of the BBB and the systemic recruitment of macrophages to the brain might be therapeutically relevant to leukoencephalopathy and other Alzheimer’s like dementias.

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

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Newly discovered immune cells at the frontline of HIV infection

mymedicplus — Sat, 22 Jun 2019 07:01:39 +0000

Source: medicalxpress.com

Researchers at The Westmead Institute for Medical Research have discovered brand new immune cells that are at the frontline of HIV infection. Known as CD11c+ dendritic cells, these new cells are more susceptible to HIV infection and can then transmit the virus to other cells.

CD11c+ dendritic cells are a subset of dendritic cells (a type of immune cell) that are only found in human genital tissues, specifically at the epithelial level (the thin layer of tissue that forms the surface) of the vagina, inner foreskin and anus. This location in genital tissue often means that these newly discovered CD11c+ dendritic cells are the first immune cells to interact with HIV.

One of the lead researchers on this project, Associate Professor Andrew Harman from The Westmead Institute for Medical Research says that the role of these newly discovered CD11c+ dendritic cells is to capture any incoming disease-causing virus or bacteria (pathogen), and then deliver it to CD4 T cells.

“CD4 T cells are responsible for driving an immune response to the pathogen. Interestingly, they are also the primary HIV target cells in which the virus replicates.

“Once dendritic cells capture a pathogen, they communicate what they have found to CD4 T cells in the lymph nodes, essentially giving the immune system a constant update. This information prepares the immune system to either tolerate a bacteria or virus, or attack it.

“However, if CD4 T cells fall below critical levels (e.g. in HIV positive patients), then the body is no longer able to mount an immune response, leading to a diagnosis of AIDS.

“Our research team has shown that the newly discovered CD11c+ dendritic cells are more susceptible to HIV infection than any other known dendritic cell. We have also shown that CD11c+ dendritic cells interact with CD4 T cells more efficiently than any other dendritic cells. Importantly CD11c+ dendritic cells transfer the virus to CD4 T cells, making them key drivers of HIV infection. As these dendritic cells are so efficient at interacting with CD4 T cells, they are also important vaccine candidates.

The team from The Westmead Institute for Medical Research were able to discover these CD11c+ dendritic cells using donated genital tissues.

Associate Professor Harman says, “We were able to look at the tissue only 30 minutes after it had been surgically removed from the body and also developed ground breaking RNAscope technology which allowed us to watch as living CD11+c dendritic cells took up the virus and delivered it to the CD4 T cells,” says Associate Professor Harman.

According to co-lead author and Executive Director of The Westmead Institute for Medical Research, Professor Tony Cunningham, this discovery has unlocked two new avenues for medical researchers to pursue in the search for more effective HIV treatments.

“This finding opens up a potential for the development of strategies to block the transmission of HIV. If we can block HIV’s ability to bind to the CD11+c dendritic cells, which are often the first immune cells to encounter the HIV virus, then we can stop their ability to transmit the virus to the CD4T cells. In a situation where there are low levels of CD4 T cells, this could stop the virus from spreading.

“Another avenue is to use this new information to develop a HIV vaccine. If HIV fragments or inactivated HIV were targeted at these CD11+c dendritic cells, this would have the potential to prime an immune response against HIV as soon as it enters the body,” says Professor Cunningham.

The post Newly discovered immune cells at the frontline of HIV infection appeared first on MyMedicPlus.

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New Mutations Discovered In Rare Dementia

Newly discovered immune cells at the frontline of HIV infection