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A change in the DNA code (mutation) of a gene that plays a key role in the brain鈥檚 immune defenses may prevent related cells from clearing away protein-filled clumps, a new study in mice shows. The buildup of such clumps, also called plaque, sets off an immune response that can kill brain cells and may lead to the dementia associated with Alzheimer鈥檚 disease. The new findings may offer a potential new target for therapies that directly affect the gene mutation, according to the study authors.
The gene in question, inositol polyphosphate-5-phosphatase D (INPP5D), contains instructions for the building of enzymes that prompt immune cells called microglia to engulf plaque, damaged pieces of brain cells, and bacteria and viruses. While past studies have linked this gene to Alzheimer鈥檚 disease, its specific role in the condition has been unclear.
The study was led by researchers at NYU Grossman School of Medicine and Icahn School of Medicine at Mount Sinai. It showed that within just 3 months, mice genetically engineered to lack the INPP5D gene in their microglia developed 50 percent more plaque deposits than mice with normal microglia, with the plaques in the mice with the mutation larger in size, on average.
鈥淥ur 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,鈥 says study co-lead author Philip Hasel, PhD, a postdoctoral research fellow in 嘿嘿视频 Health鈥檚 .
The investigation, , also revealed that more microglia clustered around plaque sites in mice missing microglial INPP5D, even though the study authors initially expected the opposite to occur. A possible explanation, they say, is that the malfunctioning immune cells could no longer effectively digest the plaque they swallowed, and as a result, more microglia were recruited to clear away the deposits.
Dr. Hasel adds that INPP5D was not the only gene explored in the investigation. The study authors also tied a group of genes to plaque buildup for the first time when they found that in INPP5D-deficient mice more than half of the genes in this group were active in cells closely linked to plaque. Notably, this cluster is known to produce molecules that trigger inflammation in Parkinson鈥檚 disease, Huntington鈥檚 disease, and various forms of dementia.
For the investigation, researchers removed INPP5D from microglia, leaving the gene intact in the rest of the animal. This process allowed them to better see the specific impact of the missing gene on brain tissue. Then they measured plaque buildup and microglial behavior roughly three months later.
Next, the study team measured gene activity in rodent brain tissue samples to determine how INPP5D interacts with other genes. They compared these findings to previous research in humans with Alzheimer鈥檚 disease, observing the same genetic changes in the gene cluster linked to plaque. This suggests that the cluster may play a similar role in brain cell death in our own species, says Dr. Hasel.
鈥淭hese results highlight the importance of ensuring that inositol polyphosphate-5-phosphatase D and the enzymes it produces are working effectively to prevent plaque buildup,鈥 says study co-senior author and neuroscientist . 鈥淚n the future, experts might be able to tailor therapies around this gene to potentially slow down the progression of conditions such as Alzheimer鈥檚 disease, glaucoma, and multiple sclerosis.鈥
Dr. Liddelow, an assistant professor in the Departments of and at 嘿嘿视频, cautions that the study authors completely deleted INPP5D in the microglia of mice, while humans with Alzheimer鈥檚 disease still retain a mutated version of the gene. He also notes that since the research team only looked at a snapshot in time, it remains unclear whether the increased plaque buildup and changes in microglial behavior also occur at other stages of the disorder.
According to Dr. Liddelow, also a member of 嘿嘿视频鈥檚 Neuroscience Institute, the study team next plans to examine exactly how microglia malfunction in the absence of INPP5D and to identify other genes that may be involved in the regulation of these immune cells.
Funding for the study was provided by National Institutes of Health grants P30AG066515, U01AG046170, RF1AG058469, RF1AG059319, R01AG061894, P30AG066514, U01AG046170, RF1AG057440, U01AG046170, and RF1AG057440. Additional funding was provided by the Blas Frangione Foundation, the Neurodegenerative Diseases Consortium from MD Anderson, Alzheimer鈥檚 Research UK, the Gifford Family Neuroimmune Consortium as part of the Cure Alzheimer鈥檚 Fund, the Alzheimer鈥檚 Association, and 嘿嘿视频鈥檚 . Further funding was provided by Paul Slavik.
Dr. Liddelow maintains a financial interest in AstronauTx Ltd., a company investigating possible treatment targets for Alzheimer鈥檚 disease. The terms and conditions are being managed in accordance with the policies of 嘿嘿视频.
In addition to Dr. Hasel and Dr. Liddelow, another 嘿嘿视频 study investigator involved in the study was Rachel Kim, BA. Other study authors were study co-lead author Emilie Castranio, PhD; Jean-Vianney Haure-Mirande, PhD; Angie Ramirez, BS; Sam Gandy, MD, PhD; and study co-senior author Michelle Ehrlich, MD, at Icahn School of Medicine at Mount Sinai in New York City.
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