Memory loss, confusion, speech problems – Alzheimer’s disease is the most common cause of dementia, affecting approximately 35 million people worldwide, and the number is growing. The protein amyloid beta, which occurs naturally in the brain, plays a central role in the disease: it accumulates in patients in insoluble clumps that form plaques between neurons in the brain, damaging them. Researchers from the Max Planck Institute (MPI) for Multidisciplinary Sciences have now shown that in addition to neurons, special glial cells in the brain also produce amyloid beta. This finding could open new avenues for future therapies.
There is no cure for Alzheimer’s disease. However, there are therapeutic approaches to reduce amyloid plaques in the brain. This can slow the progression of the disease, but not reverse or stop it. “Until now, neurons were thought to be the main producers of amyloid beta and the main target for new drugs,” explains Klaus-Armin Nave, MPI Director for Multidisciplinary Sciences. Results from his Neurogenetics department have now shown that in addition to neurons, special glial cells – called oligodendrocytes – play an important role in the formation of plaques.
“One of the jobs of oligodendrocytes is to form myelin – an insulating layer – and wrap it around nerve fibers to speed up signal transmission,” explains Andrew Octavian Sasmita, one of the first authors of the study now published in Nature Neuroscience and a former PhD student on Nave’s team. In an earlier study, the researchers from Göttingen had already discovered that defective myelin of oligodendrocytes worsens Alzheimer’s disease. Do glial cells play an even greater role in the disease than previously thought?
We have now shown that although neurons are the main producers of amyloid beta, oligodendrocytes also produce a significant amount of the protein that is incorporated into plaques.”
Andrew Octavian Sasmita, one of the first authors of the study
A research group led by Marc Aurel Busche of University College London (England) recently came to similar conclusions.
Preventing plaque formation
The cells of the nervous system produce amyloid beta by cleaving a larger precursor molecule using an enzyme called BACE1. For their experiments, the researchers specifically disabled BACE1 in the neurons and oligodendrocytes of mice. They then used 3D light microscopy to study plaque formation in the brain, providing a complete picture of amyloid plaques in all brain regions.
“Oligodendrocytes without BACE1 developed approximately 30 percent fewer plaques. Disabling the BACE1 gene in neurons reduced the formation of plaques by more than 95 percent,” says Constanze Depp, also first author of the study and a former PhD student in Nave’s department. The scientists also found: “Plaque deposits only form when a certain amount of neuronal amyloid beta is present. The oligodendrocytes then contribute to these plaques.”
This threshold could be useful for therapies for Alzheimer’s disease. “If we can successfully inhibit BACE1 before this threshold is reached, the plaques can form later,” Nave points out. That could help slow the progression of Alzheimer’s disease in its early stages.
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Magazine reference:
Sasmita, A.O. et al. (2024). Oligodendrocytes produce amyloid-β and contribute to the formation of plaques next to neurons in Alzheimer’s disease model mice. Nature Neuroscience. doi.org/10.1038/s41593-024-01730-3.