Disruption in Myelination in the Brain by APOE4

Abstract

How the brain is affected by APOE4 -one of the most important genetic risk factors in patients with Alzheimer's disease (AD), is still not clear. This missing piece is a substantial barrier to understanding the risk factors of AD and their use as therapeutic targets. Blanchard and colleagues performed a study to delineate the function of APOE4 by post-mortem transcriptomic analysis of the brains of non-carriers and carriers of APOE4. The data from their results point to the fact that APOE4 influences a host of expression profiles and signaling mechanisms in all of the studied cell types. The most significant effects were observed in the cholesterol homeostasis and transport mechanisms. It was observed that the oligodendrocytes were subjected to abnormal cholesterol metabolism, which subsequently affected the electrical activity of neurons. These results were affirmed using induced pluripotent stem cells, post-mortem human brains, and targeted replacement mice. It was also seen that altered deposition of cholesterol in APOE4 carrier brains reduced myelination. Pharmacological improvement in axonal myelination of APOE4 mice demonstrated better memory and learning. By providing a single-cell atlas of the partaking signaling events, the authors concisely represented the transcriptomic effects of APOE4. A working relationship between cholesterol transport, myelination, and subsequent effects on learning and memory with APOE4 was also provided, thus unveiling potential targets for treating AD. Nature (2022) DOI: 10.1038/s41586-022-05439-w.