Alzheimer’s Disease: It’s Not Just Neurons That Play a Role

Memory loss, confusion, language problems – Alzheimer’s disease is the most common cause of dementia and affects around 35 million people worldwide, and the number is rising. 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 the nerve cells in the brain and damage them. Researchers at the Max Planck Institute (MPI) for Multidisciplinary Sciences have now shown that, in addition to nerve cells, special glial cells in the brain also produce amyloid beta. This finding could open up new avenues for future therapies.

Not Only Neurons, But Also Specialized Glial Cells are Involved

There is no cure for Alzheimer’s disease. However, there are therapeutic approaches to reduce the amyloid plaques in the brain. This can slow the progression of the disease, but cannot reverse or stop it. “Until now, it was assumed that neurons are the main producers of amyloid beta and the main target for new drugs,” explains Klaus-Armin Nave, Director at the MPI for Multidisciplinary Sciences. The results of his Department of Neurogenetics have now shown that, in addition to neurons, specialized glial cells – so-called oligodendrocytes – play an important role in plaque formation.

“One of the tasks of oligodendrocytes is to form myelin – an insulating layer – and wrap it around nerve fibres to accelerate signal transmission,” explains Andrew Octavian Sasmita, one of the lead authors of the study now published in Nature Neuroscience and a former doctoral student in Nave’s team. In an earlier study, the Göttingen researchers had already discovered that defective myelin from oligodendrocytes exacerbates Alzheimer’s disease.

Do glial cells play an even greater role in the disease than previously assumed? The researchers 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. Similar results were recently obtained by a research group led by Marc Aurel Busche at University College London (England).

Preventing Plaque Formation

The cells of the nervous system produce amyloid beta by cleaving a larger precursor molecule with the help of an enzyme called BACE1. For their experiments, the researchers specifically switched off BACE1 in the neurons and oligodendrocytes of mice. They then used 3D light-sheet microscopy to examine plaque formation throughout the brain, thus obtaining a complete picture of the amyloid plaques in all brain regions.

According to Constanze Depp, also a first author of the study and a former doctoral student in Nave’s department, about 30 percent fewer plaques were formed in oligodendrocytes without BACE1. Knocking out the BACE1 gene in neurons reduced plaque formation by over 95 percent. The scientists also found that plaque deposition only occurs when a certain amount of neuronal amyloid beta is present. The oligodendrocytes then contribute to these plaques. This threshold could be useful for Alzheimer’s therapies. If researchers can inhibit BACE1 before this threshold is reached, the plaques could form later. This could help to slow the progression of Alzheimer’s disease at an early stage.