September 1, 2023
Keio University School of Medicine
A research group led by Professor Hideyuki Okano and Project Lecturer Hiroki Watabe of the Department of Physiology, Keio University School of Medicine, and Rei Murakami, a student in the Doctoral Programs at the university's Graduate School of Medicine, has discovered that a neurotoxic protein is secreted from astrocytes carrying a susceptibility gene for Alzheimer's disease, and that this protein damages synapses between nerve cells. The study was conducted using human iPS cell-derived astrocytes.
The type 4 allele of the apolipoprotein E (APOE) gene (APOE4) is known as a susceptibility gene for Alzheimer's disease, and its genotype frequency is estimated to be about 10% in the Japanese population. It is known that individuals with this susceptibility genotype (APOE4) are more than 3.5 times more likely to develop Alzheimer's disease than those without it. Furthermore, the loss of synapses between nerve cells is known to occur in the brains of patients in the early stages of Alzheimer's disease and is thought to be involved in the progression of the disease. Using genome editing technology, this research group generated human astrocytes with APOE4 and examined their effects on nerve cells, revealing that APOE4 astrocytes damage synapses between nerve cells. Analysis of genes with altered expression in APOE4 astrocytes indicated that a neurotoxic protein is secreted. Furthermore, specific immunocytochemical staining revealed that this secreted protein accumulates in the brains of Alzheimer's disease patients with APOE4. These findings have clarified the molecular mechanism by which APOE4 astrocytes exert detrimental effects on nerve cells.
This research successfully demonstrated the mechanism of action of an Alzheimer's disease susceptibility gene using a human iPS cell-derived neural cell model, and it is expected to lead to tailor-made drug discovery for patients with APOE4.
These research findings were published online in Stem Cell Reports , the official journal of the International Society for Stem Cell Research (ISSCR), on August 31, 2023 (U.S. Eastern Time).
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