Assessing if the brain’s insulating cells contribute to toxic clumps of protein in Alzheimer’s

One of the major types of cells in the brain are called neurons, which are important for carrying messages that allow us to think. There are many other cells that make up a healthy brain, including a type of cell called an oligodendrocyte. This cell uses finger-like processes to wrap around neurons and cover them in a fatty layer so that they can carry messages faster. For this reason, they are sometimes referred to as the insulating cells of the brain.

Every cell in the body contains DNA, the genetic sequence that tells the cell how to make the proteins it needs. There are certain genes that contribute to Alzheimer’s Disease, for example, genes that are important for making a protein called amyloid-beta. In Alzheimer’s Disease, amyloid-beta clumps together to form plaques that can damage cells and may cause problems with memory and thinking.

We know that neurons produce amyloid-beta and therefore contribute to amyloid-beta plaques. There is evidence that other types of brain cells, including oligodendrocytes, might also produce amyloid-beta, and that insulation of neurons by oligodendrocytes may be altered in the brains of people with Alzheimer’s Disease. Therefore, the researchers in this study wanted to find out if oligodendrocytes contribute to forming amyloid-beta plaques in a mouse brain.

Why is the study important?

The study is important for understanding the types of cells that produce abnormal proteins in Alzheimer’s Disease, giving us a better idea of how the disease develops in the brain. In the future, researchers could use this information to work out which cells to target when developing new treatments. Mouse brains can give us a good idea about how things work in the human brain because they are similar to human brains at the level of individual cell types and their connections. However, it is important to note that human brains are much more complex than mouse brains, therefore findings from mice are not always exactly applicable to humans.

What did the authors do and how did they do it?

First, the authors looked at data containing information about the genetic sequences from healthy mice and humans. They wanted to find out about genes that were important for making amyloid-beta. One of these genes makes a protein called BACE1.

The next step was to study mouse brains that mimicked a human Alzheimer’s Disease brain. The authors refer to these mice as ‘AD mice’ throughout the paper. They studied different groups of AD mice that did not make any BACE1 in certain types of cells. The first group of mice did not make BACE1 in neurons, the second group did not make BACE1 in oligodendrocytes, and in the third group neither type of cell made BACE1.

The authors stained amyloid-beta in the brains of each group of mice and looked at them using a microscope. They compared the number of amyloid-beta plaques in the brains of each group to the AD mice that produced BACE1 in all cell types normally. This was to determine the contributions of each cell type to the number of amyloid-beta plaques.

The genetic sequence data from humans showed that oligodendrocytes in certain areas of the brain expressed genes that are important for making amyloid-beta, including the gene for BACE1. This led the researchers to investigate BACE1 expression further in AD mice.

In the mouse brains, when only the oligodendrocytes did not produce BACE1 there were 30% less amyloid-beta plaques compared to AD mice that produced BACE1 normally. When only the neurons did not produce BACE1 there was a bigger decrease in amyloid-beta plaques of 95-98%. The authors also looked at the amount of free amyloid-beta protein that was present in the mouse brain but not clumped together in plaques. There was less free amyloid-beta in both groups of mice that lacked BACE1 than in mice with normal BACE1. Finally, in the mice where neither neurons nor oligodendrocytes made BACE1 there were almost no plaques or free amyloid-beta protein detected.

What do the findings mean going forward for people with the disease?

These findings show that oligodendrocytes, as well as neurons, are involved in the development of amyloid-beta plaques in the Alzheimer’s Disease brain. While neurons contributed more to the amount of amyloid-beta in the mice, the authors note that the effect of blocking BACE1 production in oligodendrocytes had a similar effect on the number of plaques as Lecanemab, an FDA-approved drug for Alzheimer’s Disease which reduces the amount of amyloid-beta in the brain. In the past, other researchers have targeted BACE1 across the whole brain as a treatment for Alzheimer’s disease in clinical trials, but this caused some negative side effects. Therefore, the researchers in this study think that targeting BACE1 only in oligodendrocytes could be a better alternative to try in the future, although more work would need to be done to make sure that this is safe and effective.

This study can be found at
https://www.ncbi.nlm.nih.gov/pubmed/39103558

Paper title
Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice

Lead author
Andrew Octavian Sasmita and Klaus-Armin Nave

Publication details including date of publication
5th August 2024