Brain cell study identifies new drug target to treat Alzheimer’s Disease

Inflammatory conditions in the brain, including traumatic brain injury and degenerative diseases like Alzheimer's could be targeted with an existing drug thanks to new research that shows it can work in brain cells.

In a study published in Brain, a team led by Professor Nicholas Barnes at the University of Birmingham has identified a critical receptor that when blocked inhibits neuroinflammation. This first-of-its-kind work with human brain tissue demonstrates how interrupting this pathway could open the door to treating a wide spectrum of chronic neurological conditions. These include not only traumatic brain injury (TBI), but also neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, and even psychiatric disorders such as depression and psychosis, these latter conditions are increasingly understood to have a neuroinflammatory component.

Using live cultures of human brain cells and slices of brain tissue obtained during neurosurgery, the researchers investigated the role of a receptor known as the P2X7 receptor, which is responsible for triggering inflammatory signalling.

Their findings reveal that these P2X7 receptors drive the release of key proteins called cytokines involved in controlling inflammation. By blocking this receptor with a specific antagonist, the team was able to significantly reduce the inflammatory response in human brain tissue.

Professor Nicholas Barnes from the College of Medicine and Health at the University of Birmingham and corresponding author of the paper said: “This exciting discovery marks a major step toward repurposing existing therapeutics to combat neuroinflammation at its source. The identification of this receptor could have far-reaching implications for some of the most debilitating and widespread brain disorders such as Alzheimer’s Disease, Parkinson’s and Multiple Sclerosis, or inflammation-linked psychiatric conditions like schizophrenia and depression”.

Brain’s resident immune sentinels

In order to study how brain cells respond to and manage inflammation, the team developed a way of turning a type of white blood cell into microglia, replicating a normal cellular transformation that has recently been identified to occur in the brain as a natural part of human ageing. These microglia are the central coordinators of the immune system in the brain.

Using readily accessible human peripheral monocytes taken from blood samples, the researchers converted them into microglia-like cells that were used to see how microglia are likely to respond to the inflammation signals. Using the P2X7 receptor antagonist, the team were then able to interrupt the triggers that these microglia give off as they are damaged and die.

Professor Barnes said: “Studying human microglia has long been a major challenge: once removed from their native brain environment, they rapidly lose their defining characteristics, likely due to the absence of critical regulatory signals. Our approach involved the use of monocyte-derived microglia which provide a powerful, scalable, and virtually unlimited platform for studying human microglial biology with unprecedented precision.

“Having identified the response in the human monocyte-derived microglia, this provided the impetus to translate these findings with human brain obtained following neurosurgical procedures. This successful translation means the next stage for this research is the development of clinical trials in patients with neurodegenerative conditions and patients with TBI where there are no effective pharmacological treatments to reduce the neuroinflammation and arising damage.”