The many types of lipids of the body have countless functions and tasks. “That's why proper control of lipid levels is essential for human health”, says Professor Thomas Willnow who presented his research at the Society for Neuroscience conference on November 6, 2018. “Alterations in lipid levels result in devastating diseases that impact heart and blood vessels, but also the aging brain.”
Case in point: a brain protein that carries lipid molecules as a cargo, Apolipoprotein E (apoE). “ApoE is the most important genetic risk factor for Alzheimer's disease”, Willnow says. It is present in three variations in humans called E2, E3 and E4. It has long been known that the variant E4 confers a high risk of Alzheimer’s disease whereas the common variant E3 does not.
His latest research now shows that in order to be protective, the apoE3 variant is dependent on the receptor molecule “sortilin”. This receptor helps control the lipid cholesterol in the blood, but it also helps neurons to take up lipids through apoE in the brain.
The scientists' new findings now suggest that apoE4 cannot interact with sortilin and therefore does not possess the protective activity shown by apoE3. The findings may explain why people who carry the gene for E4 are at an almost eight-fold higher risk to develop the disease compared to those carrying E3.
Studying the function of Apolipoprotein in the brain
For their experiments, the researchers introduced a gene defect into the sortilin gene of mice which produced either human apoE3 or apoE4. Subsequently, they analyzed lipid levels in the brain of these mice and compared them to animals still expressing sortilin.
Depending on the presence of sortilin, the animals producing apoE3 showed major differences in brain lipid composition. Furthermore, apoE3 mice without sortilin had substantially increased levels of neurotoxic A-beta peptides in the brain – a hallmark of Alzheimer's disease. By contrast, the differences between mice with the apoE4 variant were relatively minor: The changes in the lipid profiles were small and the loss of sortilin did not influence the already high levels of the neurotoxic peptides.
A protective protein
Sortilin is required for the neuroprotective function of apoE3 in brain lipid metabolism, the researcher summarizes. “The very same receptor sortilin controls lipid homeostasis in the brain and in the blood stream, thereby protecting from both cardiovascular and neurodegenerative diseases.“ This may offer common therapeutic strategies for treatment of both types of diseases that represent major threats to human health.
How exactly apoE3 and sortilin maintain a healthy brain lipid composition and reduce neurotoxic A-beta levels is not yet known. Willnow says that projects in his lab are currently investigating this question. Speaking at a large conference like the 2018 meeting of the Society for Neuroscience helps driving these projects forward by establishing collaborations with scientists working on related topics.