The gene coding for APOE exists in three frequent versions in people: APOE2, present in 8% of the population, APOE3, the most common, and APOE4, which is found in nearly 15% of individuals and increases the threat of developing Alzheimers illness by a factor of ten. “The factors why APOE4 increases the danger of Alzheimers illness so significantly are not well comprehended,” discusses Anne-Claude Gavin, a professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine and holder of a Louis-Jeantet Foundation Chair, who directed this research together with Viktor Lakics, a Research fellow and Biology Area Leader in Neuroscience discovery at AbbVie.
A protein that is too efficient
Working on these concerns, the research study team determined novel molecular systems that discuss how APOE binds to astrocyte membranes to discover and draw out the lipids it needs. Employing human cell lines with different APOE versions, in vitro experiments demonstrated that APOE is very effective at carrying possibly harmful lipids produced in nerve cells. “And to our terrific surprise, the APOE4 alternative showed to be even more efficient than the other kinds,” exposes Katharina Beckenbauer, a former post-doc in Anne-Claude Gavins group, senior researcher at AbbVie, and among the very first authors of the work. “So, contrary to what we believed until now, the issue is not that APOE4 quits working, however, in truth, the opposite. And the mechanism goes crazy.”
A pirated function
As astrocytes age, they end up being less efficient and begin to collect lipids rather than destroy them. “We designed this procedure experimentally and observed the molecules secreted by the astrocytes,” discusses Karina Lindner, a PhD trainee in Anne-Claude Gavins lab and one of the very first authors of this work. This deleterious build-up of possibly damaging lipids could extremely well be an essential contributor to the neuronal death, a trademark of Alzheimers disease.
In order to better comprehend the information of the action of APOE and specifically of the E4 version, the scientists at UNIGE want now to determine how secretion of these potentially damaging lipids is controlled and whether this secretion can be discovered in individuals suffering from Alzheimers illness.
Referral: “Isoform- and cell-state-specific lipidation of ApoE in astrocytes” by Karina Lindner, Katharina Beckenbauer, Larissa C. van Ek, Kevin Titeca, Sherida M. de Leeuw, Khader Awwad, Franziska Hanke, Alla V. Korepanova, Vladimir Rybin, Elizabeth Louise van der Kam, Eric G. Mohler, Christian Tackenberg, Viktor Lakics and Anne-Claude Gavin, 1 March 2022, Cell Reports.DOI: 10.1016/ j.celrep.2022.110435.
Left: regular astrocyte able to destroy hazardous lipids produced by nerve cells.: an astrocyte that stores lipids in beads (pink) and begins secreting hazardous lipids in the surrounding tissue. By triggering astrocytic lipid secretion, it causes the accumulation of potentially hazardous lipids that are hazardous to nerve cells, and hence may contribute to the advancement of Alzheimers illness. Working on these questions, the research group recognized novel molecular systems that describe how APOE binds to astrocyte membranes to identify and extract the lipids it requires. As astrocytes age, they end up being less efficient and start to collect lipids rather than destroy them.
Left: regular astrocyte able to ruin hazardous lipids produced by nerve cells. : an astrocyte that stores lipids in beads (pink) and starts producing toxic lipids in the surrounding tissue. Credit: UNIGE/ A.-C. Gavin
A European consortium coordinated by UNIGE demonstrates how an anomaly in the APOE protein changes the lipid transport in the brain and could promote the emerge of Alzheimers disease.
Neurons in the brain exist side-by-side with and rely on many other cell types to operate appropriately. Astrocytes, which take their name from their star shape, make sure the survival of nerve cells by feeding and cleansing them with the aid of a multifunctional protein, APOE. One of 3 kinds of this protein, APOE4, significantly increases the threat of establishing Alzheimers disease, however the systems at play are unidentified. A partnership between the University of Geneva (UNIGE), the European Molecular Biology Laboratory (EMBL), the University of Zurich and the pharmaceutical company AbbVie has actually found a possible mechanism: far from ceasing to operate, APOE4 is, on the contrary, more effective. By setting off astrocytic lipid secretion, it causes the build-up of potentially toxic lipids that are hazardous to nerve cells, and thus might contribute to the advancement of Alzheimers illness. These results released in the journal Cell Reports, shed new light on the neurodegenerative systems of a disease that impacts nearly 50 million people worldwide.
Astrocytes, present in huge numbers in the brain, have a major protective function. These cells secrete apolipoprotein E (or APOE), a small protein that forms particles containing vitamins and lipids to feed the neurons. It also cleanses the nerve cells by getting them eliminate “lipid waste” that might become damaging if not gotten rid of. As the nerve cells are not able to eliminate this waste by themselves, APOE enters into play to collect it and bring it back to the astrocytes where it is destroyed.