Oligodendrocytes’ unexpected role in the fight against Alzheimer’s Disease
Dr Marc Aurel Busche and his team discovered something unexpected - that oligodendrocytes not just neurons produce amyloid beta, a finding which has promise for future Alzheimer's disease treatments.
Dr Marc Aurel Busche, Group Leader at the UK Dementia Research Institute at UCL
One afternoon, Dr Marc Aurel Busche, a clinician scientist and Group Leader at the UK Dementia Research Institute at UCL, and his team noticed something strange about their cell data. They were verifying data on which cells in the brain contain the machinery to produce amyloid beta, tiny protein fragments that can clump together and produce amyloid plaques found in the brains of people with Alzheimer's disease. They were anticipating that neurons would be the primary source, as widely believed. To their surprise, oligodendrocytes, cells known for their role in insulating nerve fibers, exhibited all the necessary components for amyloid beta production, and at levels even higher than neurons.
“This discovery was quite unexpected and serendipitous really” notes Dr Marc Aurel Busche “and this finding prompted us to investigate the role of oligodendrocytes in Alzheimer’s disease further.”
Alzheimer’s disease is a devastating, progressive neurodegenerative disorder affecting millions of people worldwide. One of the early hallmarks of the disease in the accumulation of amyloid beta, which can start up to 30 years before the symptoms of Alzheimer’s appear. This makes amyloid beta an important target for understanding the pathophysiology of the disease and for investigating treatments to slow progression.
Up until this point, previous research had primarily been focused on the role of neurons in the production of amyloid beta. “Previous research has shown that neurons, especially those that are more active, produce more amyloid beta, which in turn makes these neurons even more hyperactive - a vicious cycle our group and others identified over a decade ago. Our new findings indicate that this concept needs revision. We discovered that the early production and release of amyloid beta is more complicated and involves not just neurons but also oligodendrocytes.”
This new insight is exciting, not only because it adds another layer to our understanding of Alzheimer’s disease, but also because targeting amyloid beta production specifically in oligodendrocytes offers a novel therapeutic avenue, with potentially fewer side effects for patients.
“Previous clinical trials aimed at reducing amyloid beta production in neurons showed promise but also worsened cognition in patients, likely because these treatments interfered with crucial neuronal functions, such as synaptic connectivity. Oligodendrocytes, however, do not have these same structures, which means that therapies targeting amyloid beta production in these cells could potentially avoid these adverse effects.”
Patient care is top of mind for Dr Marc Aurel Busche who, as well as running a research laboratory at the UK DRI at UCL, is also a clinician, caring for people with Alzheimer’s Disease. This is a dual role he finds to be a unique privilege. “It is incredibly fulfilling because it allows me to directly apply insights from the lab to address the real-world challenges my patients face, while also bringing clinical observations back to the lab for investigation with the highest-quality science.”
Scientist captures images of human oligodendrocytes in a dish (stained green), which produce the protein implicated in causing Alzheimer's disease
Looking to the future of Alzheimer’s treatments, Dr Marc Aurel Busche is optimistic about where research into oligodendrocytes could lead:
“Existing therapies for Alzheimer’s disease focus on reducing amyloid plaques that have already formed in the brain. While these appear effective in slowing cognitive decline, these treatments can increase the risk of side effects, including brain bleeding. Our approach is different; we aim to prevent amyloid beta from accumulating into plaques in the first place by targeting its production specifically in oligodendrocytes. This strategy could potentially reduce the risk of side effects, as it would target the disease process at an earlier stage and in a more cell-specific manner. We believe that by focusing on the source of amyloid beta production rather than its end products, we can develop treatments that are both safer and more effective.”