On the left, a functional astrocyte capable of destroying toxic lipids produced by neurons. On the right, an astrocyte storing lipids in droplets (in purple) and secreting toxic lipids into the surrounding tissue.
The role of the APOE4 protein in the onset of Alzheimer's, whose link with the late form of the disease was known, is now better understood thanks to the work of Swiss scientists.
Researcher Karina Lindner and her colleagues from the universities of Geneva and Zurich have shown how this protein modifies lipid transport and contributes to the emergence of neurodegenerative disease.
- The apolipoprotein E (APOE) is a protein produced by a gene located on chromosome 19.
- There are three forms of the APOE gene, comprising the ε2, ε3 and ε4 alleles.
- These alleles thus produce three different forms of APOE-like proteins (APOE2, APOE3 and APOE4).
- APOE4 is associated with a greater risk of late onset Alzheimer's.
Proper functioning of neurons in the brain depends on many other types of cells, including astrocytes. These star-shaped cells, present in large numbers in the brain, ensure the survival of neurons by nourishing them and detoxifying them using the APOE protein they secrete.
This protein ensures the detoxification of neurons by ridding them of their lipid waste, which can become harmful. Since neurons are unable to eliminate this waste on its own, APOE comes into play to collect it and bring it back to the astrocytes, where it is destroyed.
About 15% of people have the APOE4 form of the protein, which increases their risk of developing the disease tenfold.
So far, no study had managed to clearly establish the mechanisms that link APOE4 to Alzheimer's, but some researchers argued that the protein stopped working properly. The present work shows that it is quite the opposite, and that it is in fact too efficient.
This protein, by triggering the lipid secretion of astrocytes, causes the accumulation of lipids harmful to neurons, which contributes to the appearance of the disease, note in a press release the authors of this work published in the journal Cell Reports.
Work that identified new molecular mechanisms that explain how APOE binds to membranes astrocytes to detect and extract the lipids it needs.
Experimentsin vitroconducted on human cell lines carrying different variants of APOE have also shown that this protein is extremely effective in transporting potentially harmful lipids produced in neurons.
“To our surprise, APOE4 was found to be even more effective than other forms of the protein. So, contrary to what we thought so far, the problem is not that APOE4 stops working, but the opposite: the mechanism goes into overdrive.
— Katharina Beckenbauer, study co-first author
As astrocytes age, they become less efficient and begin to accumulate lipids rather than destroy them , explain the researchers.
We experimentally modeled this process and observed the molecules secreted by astrocytes, explains Karina Lindner, also co-first author of this work.
This experiment allowed the researchers to observe how cellular aging diverts APOE from its primary function, i.e. the transport of lipids to neurons and the recovery of lipid waste, towards the secretion of triglycerides, lipids that can become harmful s 'they are not destroyed.
In addition, the researchers determined that this phenomenon is exacerbated with APOE4, which stimulates the secretion of triglycerides, leading to their uncontrolled accumulation.
This accumulation could, according to the researchers , contribute to the death of neurons, one of the hallmarks of Alzheimer's disease.
“APOE4 would thus present the ability to accelerate the pathological process of the disease.
— Researcher Karina Lindner
The team will now work to better detail the action of APOE and especially its variant E4. Its objective is to find out how the secretion of these potentially harmful lipids is regulated and whether this secretion can be detected in people suffering from Alzheimer's disease.
Alzheimer's is the most common cause of dementia. No less than 564,000 Canadians currently have Alzheimer's or a related disease. In 15 years, there will be 937,000, estimates the Alzheimer Society of Canada.