Brain cell gene changes linked to neuroinflammation seen in Alzheimer’s
New research has revealed how genetic changes in a specialized population of brain cells called microglia contribute to neuroinflammation and, in turn, to Alzheimer’s disease. The findings could lead to more effective, targeted therapeutics.
Microglia – immune-regulating brain cells – and neuroinflammation are known to contribute to the development and progression of Alzheimer’s disease (AD). While microglia are involved in the process of neuroinflammation, the molecular pathways linking the two are not well understood.
In a new study, researchers from Brigham and Women’s Hospital (BWH) have explored these pathways and discovered how genetic changes in microglia contribute to neuroinflammation and, in turn, to AD.
“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,” said Tracy Young-Pearse, the study’s corresponding author. “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.”
Previous studies suggested that the inositol polyphosphate-5-phosphatase D (INPP5D) gene, expressed in microglia, was associated with Alzheimer’s risk, so that’s what the researchers looked into. Analyzing human brain tissue from patients with AD, they found seemingly conflicting results. While bulk levels of the INPP5D gene were elevated in AD and associated with amyloid beta plaque-associated microglia, INPP5D protein levels were dramatically reduced. This suggested that, despite the higher number of genes, the INPP5D protein was functionally inactive.
Using living human brain cells derived from stem cells, the researchers studied the molecular interactions that mediated the inflammatory process when INPP5D was reduced, identifying specific proteins that could be inhibited to block inflammasome activation in microglia. Inflammasomes are innate immune system receptors/sensors that activate inflammatory responses.
Whether INPP5D is a suitable target for therapeutics is yet to be determined. The study’s findings suggest that INPP5D activity in AD brains is complex, and further studies are needed to understand if targeting INPP5D would prevent the cognitive decline seen in the disease.
“Our results highlight an exciting promise for INPP5D, but some questions still remain,” Young-Pearse said. “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.”
The study was published in the journal Nature Communications.