Lay summary by Steaphan Connell reviewed by Dr Ryan West and by a Dementia lay panel.
Background
Alzheimer’s Disease is caused by neurodegeneration, meaning brain shrinkage from the death of nerve cells. This leads people living with Alzheimer’s Disease to experience problems with memory and thinking skills. A major feature of Alzheimer’s Disease is the accumulation of two proteins called amyloid and tau in the brain. However, it is not yet understood how or whether they cause the death of nerve cells.
Researchers can test how human nerve cells may react in Alzheimer’s Disease by planting them into mice brains with Alzheimer’s-like conditions. By using this technique, the researchers in this study could look at how human nerve cells reacted when there was an accumulation of amyloid proteins but without the tau proteins.
Why is the study important?
By seeing how human nerve cells reacted to an accumulation of amyloid proteins, the researchers can better understand the importance of these proteins in Alzheimer’s Disease. The researchers also looked at individual genes to see which ones were more active in Alzheimer’s-like conditions. This is important as it could show which genes influence Alzheimer’s Disease and could be targeted for treatments.
What did the authors do and how did they do it?
The authors planted human nerve cells into mice brains with accumulated amyloid proteins in them and monitored the mice using different brain scans. The human nerve cells in these mice were compared to human nerve cells planted in healthy mice brains (without the accumulation of amyloid proteins).
What are the results?
The mice brains with accumulated amyloid proteins also contained more tau proteins in them, as well as in the blood (which is also seen in human Alzheimer’s Disease). Around 50% of the human nerve cells died, which was significantly more than the human nerve cells in the healthy mice brains. These results suggest that the accumulation of amyloid proteins can lead to the other key features of Alzheimer’s Disease as well.
When the researchers looked at the individual genes they found higher levels of genes that are involved in a specific type of cell death called necroptosis. The gene with the biggest increase was the MEG3 gene, which has been linked to cell death in previous studies and associated with Huntington’s Disease. This study is the first to associate MEG3 and necroptosis with Alzheimer’s Disease.
The researchers conducted tests to see the effect of blocking the MEG3 gene in the mice. They also tried using drugs that block the RIPK1 and RIPK3 proteins, which are involved in a later stage of necroptosis. They found that blocking MEG3 and RIPK3 reduced nerve cell death.
What do the findings mean going forward for people with the disease?
This study is the first to associate the MEG3 gene and the necroptosis cell death process with Alzheimer’s Disease, which opens them up as new targets for testing new treatments, as well as the accumulations of amyloid and tau proteins.
This study can be found at:
https://www.science.org/doi/10.1126/science.abp9556
Paper Title:
MEG3 activates necroptosis in human neuron xenografts modelling Alzheimer’s disease.
Primary and Senior Author:
Sriram Balusu, and Bart De Strooper
Publication details including date of publication:
Science 381, 1176–1182 (2023)