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The special importance of ApoE for the formation of myelin sheaths in the brain


As described last week, apolipoprotein variant E4 (ApoE4) is the most important risk factor for the development of Alzheimer's disease. In the brain, ApoE is produced mainly by astrocytes and serves as an important binding partner of lipids to maintain synaptic integrity and enable injury repair. However, it is also found in aging and degenerating neurons.


A study by Blanchard and colleagues, recently published in Nature, now links ApoE4 to faulty cholesterol processing. As an essential building block of the lipid-containing cell membrane, this causes defects in the insulating sheaths of nerve fibers, the myelin. It is required for rapid electrical activity between nerve cells, and disturbances in cholesterol metabolism can lead to memory and learning deficits. As reported by the group around neuroscientist Li-Huei Tsai of the Massachusetts Institute of Technology (MIT) in Cambridge, ApoE4 causes cholesterol to accumulate in the wrong place in the myelin sheath-forming glial cells, the oligodendrocytes, and thereby interferes with myelin formation.


At the outset of their work, the paper's authors first analyzed patterns of gene activity in tissue samples from the prefrontal cortex (an important cognitive center in the brain) and established cell cultures of human oligodendrocytes with different forms of the ApoE gene. Cells with the ApoE4 variant tend to hoard cholesterol in cellular organelles and not transport it into the myelin sheaths.


Interestingly, treatment of the cells with the drug cyclodextrin, which stimulates cholesterol breakdown, restored myelin formation to normal. In mice with two copies of ApoE4, cyclodextrin improved cholesterol transport into the myelin sheaths, thereby enhancing the animals' cognitive performance. However, cyclodextrin is not suitable for humans because it removes too much cholesterol from the cells.


In another study relevant in this context, Liu and colleagues were able to show in Nature Neuroscience that peripheral ApoE isoforms, which do not actually enter the brain through the blood-brain barrier, have an influence on the pathogenesis of Alzheimer's disease. They studied mice that produced human ApoE3 or ApoE4 in the liver but no ApoE in the brain. Interestingly, peripheral ApoE4 also impaired synaptic plasticity and cognition.


By generating protein profiles from blood plasma, the authors demonstrated that cell adhesion, lipoprotein metabolism, and complement activation were altered depending on the particular ApoE isoform. ApoE3 plasma from young mice improved cognitive abilities and reduced vascular-associated gliosis when transfused into older mice, whereas ApoE4 prevented the beneficial effects of juvenile plasma. Finally, peripheral ApoE4 worsens amyloid pathology in the brain, whereas ApoE3 tends to ameliorate it.


Taken together, the present results underscore a pathogenic effect of ApoE4 and provide the basis for treatment of Alzheimer's disease by targeting not only central but also peripheral ApoE4.


References:


Blanchard JW, Akay LA, Davila-Velderrain J, ... , Tsai LH (2022) ApoE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 611:769


Liu CC, Zhao J, Fu Y, Inoue Y, ... , Bu G (2022) Peripheral ApoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function. Nature Neuroscience 25:1020


Image credit: iStock/wildpixel

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