The researchers discovered how genetic alterations in specific types of brain cells may lead to the inflammatory response found in Alzheimer’s disease. Brigham and Women’s Hospital researchers discovered how genetic abnormalities in particular types of brain cells may lead to the inflammatory response found in Alzheimer’s disease.
Microglia, immune-regulating brain cells, have been linked to the progression of Alzheimer’s disease (AD). A new study from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, investigates how the genetics of microglia contribute to neuroinflammation and, ultimately, Alzheimer’s disease.
The team revealed that a reduction of INPP5D, a gene found in microglia, results in neuroinflammation and increases the risk for AD. Their results, which have important implications for the design of microglia-centered therapeutics for Alzheimer’s disease and related disorders, are published in Nature Communications.
Our results highlight an exciting promise for INPP5D, but some questions still remain. Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD.
Tracy Young-Pearse
“We know that microglia play important roles in the healthy and diseased brain, but the molecular mechanisms underlying this relationship are often poorly understood,” said corresponding author Tracy Young-Pearse, PhD, of Brigham and Women’s Hospital’s Department of Neurology.
“If we’re able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics.”
Neuroinflammation is vital to monitor in persons suffering from neurodegenerative disorders, although it can be difficult to identify, particularly in the early stages of Alzheimer’s disease. The sooner neurologists recognize it, the sooner it can be treated. Microglia are definitely engaged in the process of neuroinflammation, but many questions about the molecular processes involved remain unsolved.
The team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. As part of their study, the team compared human brain tissue from patients with AD and a control group. They found lower levels of INPP5D in the tissues of patients with AD and when INPP5D was reduced, it activated inflammation.
In parallel, they used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D.
These investigations revealed particular proteins that may be blocked to prevent inflammasome activation in microglia. Although the team’s findings provide the most complete research of INPP5D in the AD brain, it remains to be determined if INPP5D should be addressed with therapies.
“Our results highlight an exciting promise for INPP5D, but some questions still remain,” she added. “Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD.”
