Researchers improving treatments for degenerative brain diseases

QIMR Berghofer scientists led by Associate Professor Anthony White are investigating how the brain’s own immune system drives neurological diseases such as dementia, motor neuron disease, and Huntington’s disease.

Despite many decades of research, there is currently no effective treatment for degenerative brain disease including dementia. There are many reasons for this, but new insights into these diseases have uncovered important roles for the brain’s own specialised immune cell, the microglia, in driving the disease process. Microglia have important roles in maintaining connections between nerve cells (preserving memory function) and repairing damage or fighting infection. However, in degenerative brain diseases, it appears that microglia function is abnormal, and these key cells start to attack the neurons that they are supposed to preserve.

The reason for this is unclear and therefore it has been difficult to identify new drugs to normalise microglia activity. A major part of the problem has been a lack of suitable model systems to understand human microglia. Animal microglia behave very differently to human microglia, especially as we age. It is not practical to collect microglia from the living human brain, so new techniques to grow human microglia in the lab have recently been developed.

Our research has centred on a new approach involving the growth of microglia from blood monocytes. This allows us to examine how microglia function in people with different degenerative brain diseases including dementia, motor neuron disease (MND), and more recently, Huntington’s disease, by simply taking a blood sample.

Research carried out by QIMR Berghofer post-doctoral researcher, Dr Hazel Quek, has already uncovered new insights into microglia behaviour in degenerative brain disease, particularly impairment of the ability of microglia to clear away damaged cells, aggregated proteins, and other unwanted material before it becomes toxic to neurons (known as phagocytosis).

Our researchers are using these models to test several exciting new drug targets to see if we can restore normal microglia phagocytosis. This project has been further enhanced by a collaboration with Professor Eske Derks and Dr Zac Gerring also at QIMR Berghofer, who have developed a new computational approach to identifying the best drugs to test in our models.

This work is now establishing a system where we can first screen drugs for their therapeutic effects on microglia in 2D (where we can screen larger numbers of drugs) and then confirm the best drug options in our 3D model to ensure they continue to work in a more complex brain-like environment.

Researchers are also growing mini-brains, called brain organoids, which have an even more complex brain-like structure. Leading drug candidates are then tested in this final platform to provide a third degree of support for potential success in the human brain.

Together with our platforms designed to test whether drugs can penetrate the brain (by crossing the blood brain barrier), we are applying a holistic or whole brain approach to drug testing. Combined with our drug testing on patient microglia, we believe this has the potential to greatly improve translation of drug action to the clinic for treatment of people with degenerative brain diseases.