Researchers Fix Alzheimer's Gene

A study published in Nature Medicine demonstrates for the first time how the most well-known genetic risk factor for Alzheimer's disease manifests in human brain cells, and how the gene can be corrected, reports Medical News Today . The researchers sought to locate and understand the fine yet crucial difference between the E3 and E4 variants of the apolipoprotein (APOE) that makes the APOE4 gene so destructive. They simulated the disease in human cells, examining the effect of APOE4 on human brain cells. The team applied stem cell technology to skin cells from people with Alzheimer's who had two copies of the APOE4 gene in order to create neurons. They determined in human brain cells, the APOE4 protein has a "pathogenic conformation" that prevents it from functioning properly, leading to various disease-causing problems. "APOE4-expressing neurons had higher levels of tau phosphorylation, which was unrelated to their increased production of amyloid-beta peptides, and ... they displayed GABAergic neuron degeneration," the researchers noted. They then compared neurons that did not generate either the E3 or the E4 variants with cells that had APOE4 added to them. The former continued to behave normally, while adding APOE4 led to Alzheimer's-like pathologies. The researchers fixed the faulty gene using a previously developed APOE4 "structure corrector" This rearranged the structure of APOE4 so that it looks and behaves more like the APOE3. Applying this compound to human APOE4 neurons corrected the defects.