Alzheimer’s disease is the leading cause of dementia, impacting approximately 35 million people globally, and this number is on the rise. A key player in this disease is the amyloid beta protein, which is naturally found in the brain. In patients, it builds up in clusters that create plaques between brain neurons, causing damage. Researchers at the Max Planck Institute (MPI) for Multidisciplinary Sciences have discovered that, along with neurons, specific glial cells in the brain also generate amyloid beta. This revelation could pave the way for innovative therapeutic approaches in the future.
Currently, there is no cure for Alzheimer’s disease, but there are treatment strategies aimed at reducing the amyloid plaques in the brain. Such approaches may slow the disease’s progression, although they cannot reverse or stop it. “Previously, it was believed that neurons were the primary source of amyloid beta and were the main focus for new drug developments,” says Klaus-Armin Nave, Director at MPI for Multidisciplinary Sciences. Recent findings from his Neurogenetics department suggest that special glial cells known as oligodendrocytes also significantly contribute to the formation of plaques.
“Oligodendrocytes are responsible for producing myelin, which acts as insulation around nerve fibers and enhances the speed of signal transmission,” notes Andrew Octavian Sasmita, one of the primary authors of the study published in Nature Neuroscience and a former PhD student in Nave’s team. Previous research by the Göttingen team had revealed that impaired myelin from oligodendrocytes worsens Alzheimer’s disease. Could it be that glial cells are more involved in the disease than was previously thought?
“Our findings indicate that although neurons are the main source of amyloid beta, oligodendrocytes also produce a considerable amount of this protein that gets deposited into plaques,” states Sasmita. Similarly, a research group led by Marc Aurel Busche from University College London (England) has reached comparable conclusions.
Preventing plaque formation
Nerve cells generate amyloid beta by cleaving a larger precursor molecule using an enzyme called BACE1. In their experiments, the researchers specifically eliminated BACE1 in neurons and oligodendrocytes of mice. They then utilized 3D light-sheet microscopy to analyze plaque formation across the entire brain, offering a comprehensive view of amyloid plaques in all brain areas.
“Oligodendrocytes without BACE1 showed about 30 percent fewer plaque formations. Meanwhile, removing the BACE1 gene in neurons led to a reduction in plaques by over 95 percent,” explains Constanze Depp, another primary author of the study and a former PhD student in Nave’s department. The scientists also discovered: “Plaque formations only occur once a specific amount of neuronal amyloid beta is present. Oligodendrocytes then contribute to these plaque developments.”
This threshold may be significant for Alzheimer’s therapies. “If we can effectively inhibit BACE1 before reaching this threshold, plaque formations might be delayed,” Nave highlights. This could aid in slowing the advancement of Alzheimer’s disease in its early stages.
