New evidence INPP5D (inositol polyphosphate-5-phosphatase D), an Alzheimer’s disease risk gene, plays a critical role in enabling microglial cells to defend the brain against plaque buildup.

A new mice study shows that a mutation in a gene that is essential for the brain’s immunological defenses may impede related cells from removing protein-filled clumps. Such accumulations, also known as plaque, may trigger an immunological response that can damage brain cells and cause dementia, which is a symptom of Alzheimer’s disease.

According to the study authors, the new discoveries could be a possible new target for treatments that specifically target gene mutation.

INPP5D (inositol polyphosphate-5-phosphatase D) is a gene that carries instructions for the creation of enzymes that cause immune cells termed microglia to ingest plaque, injured brain cells, bacteria, and viruses. Even though this gene has been linked to Alzheimer’s disease in the past, it’s not clear what role it plays in the disease.

New York University’s Grossman School of Medicine and Mount Sinai’s Icahn School of Medicine collaborated to conduct the study. Mice with a genetically engineered deficiency of the INPP5D gene in their microglia revealed 50% higher plaque deposits after 3 months compared to animals with normal microglia, with the average plaque size being bigger in the mice with the mutation.

“Our findings provide new evidence that inositol polyphosphate-5-phosphatase D plays a critical role in enabling microglial cells to defend the brain against plaque buildup,” adds co-lead author Philip Hasel.

The research, which was published today in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, also found that mice lacking microglial INPP5D had an increased number of microglia concentrated near plaque locations. They hypothesize that additional microglia were recruited to clean away the deposits because the defective immune cells could no longer efficiently digest the plaque they ingested.

Hasel says that the investigation looked at more than just INPP5D. More than half of the genes in this group were discovered to be active in cells directly connected to plaque in INPP5D-deficient mice, which provided the first direct relationship between a set of genes and plaque development. Notably, this cluster has been linked to the production of chemicals that cause inflammation in the Parkinson’s, Huntington’s, and other types of dementia.

In order to conduct the study, scientists took INPP5D out of microglia while keeping the gene unaltered in the rest of the animal. This process helped them figure out what the missing gene did to the brain tissue. Three months later, they evaluated plaque development and microglial activity.

To understand how INPP5D interacts with other genes, the research team next evaluated gene activity in rodent brain tissue samples. They compared these results to research they had already done on humans with Alzheimer’s disease and found that the gene cluster linked to plaque had changed in the same way. Hasel says this shows that the cluster may play a similar role in the death of brain cells in our own species.

“These results highlight the importance of ensuring that inositol polyphosphate-5-phosphatase D and the enzymes it produces are working effectively to prevent plaque buildup,” explains study co-senior author and neuroscientist Shane Liddelow. “In the future, experts might be able to tailor therapies around this gene to potentially slow down the progression of conditions such as Alzheimer’s disease, glaucoma, and multiple sclerosis.”

According to Liddelow, an assistant professor in the Departments of Neuroscience and Physiology and Ophthalmology at NYU Langone, the research authors entirely removed INPP5D in mouse microglia, but people with Alzheimer’s disease still have a mutant variant of the gene. He also points out that since the study only looked at one point in time, it is unknown if the increased plaque formation and changes in microglial behavior occur at other phases of the condition.

According to Liddelow, who is also a member of the Neuroscience Institute at NYU Langone, the research team will investigate how microglia malfunction in the absence of INPP5D and find other genes that may be involved in the control of these immune cells.

Image Credit: Brian B. Bettencourt/Toronto Star via Getty Images


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