Neuroinflammation’s key role in Alzheimer’s revealed

Microglia and neuroinflammation play an essential role in the development and progression of Alzheimer’s disease (AD). In individuals with neurodegenerative disorders, neuroinflammation is crucial to track, but it can be challenging to identify, particularly in the early stages of Alzheimer’s disease. Neurologists can treat it sooner if they can diagnose it more quickly. Although the involvement of microglia in neuroinflammation is well established, there are many unanswered questions regarding the molecular pathways involved. 

Using several experimental approaches, scientists at Brigham and Women’s Hospital have probed the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. They revealed genetic changes in specific types of brain cells could lead to the inflammatory response seen in Alzheimer’s disease.

Scientists found that a reduction in the microglial gene INPP5D leads to neuroinflammation and increases the risk for AD. This finding could lead to better microglia-centered therapeutics for Alzheimer’s disease and related disorders.

Corresponding author Tracy Young-Pearse, Ph.D., from the Department of Neurology at Brigham and Women’s Hospital said, “We know that microglia play important roles in the healthy and diseased brain, but, in many cases, the molecular mechanisms underlying this relationship are poorly understood. If we can identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics.”

Scientists tracked the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. They compared human brain tissue from patients with AD and a control group.

The tissues of AD patients had lower amounts of INPP5D, and when INPP5D was decreased, inflammation was triggered. Simultaneously, they studied the complex molecular interactions inside microglia that mediate inflammatory processes with a reduction of INPP5D using living human brain cells generated from stem cells. These investigations revealed particular proteins that may be blocked to prevent microglia from activating their inflammasomes. 

While the team’s findings offer the most thorough examination of INPP5D in the AD brain, it still needs to be determined if treatments should target INPP5D. This highlights the need for further research to determine whether INPP5D can be targeted to prevent cognitive deterioration in people with AD because their results indicate that INPP5D activity in AD brains is complex.

Young-Pearse said, “Our results highlight an exciting promise for INPP5D, but some questions 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.”

Journal Reference:

1. Chou, V., Pearse, R.V., Aylward, A.J. et al. INPP5D regulates inflammasome activation in human microglia. Nat Commun 14, 7552 (2023). DOI: 10.1038/s41467-023-42819-w