February 22, 2021
Keio University School of Medicine
A research group led by Project Lecturer Hiroki Watanabe and Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine, has discovered that there are several subtypes of the machinery that produces brain "waste," which is considered to be the cause of Alzheimer's disease, using human iPS cell-derived neurons.
It is known that "waste" in the form of abnormal aggregates composed of amyloid-beta (Aβ) accumulates in the brains of patients with Alzheimer's disease, and this is thought to contribute to the onset of the disease. This research group focused on the fact that there are two types (PS1 and PS2) of the catalytic subunit presenilin (PS), which constitutes the γ-secretase complex that produces Aβ. Using genome editing technology, they succeeded for the first time in the world in developing a human neuron model in which each catalytic subunit or both were deleted.
Upon examining the Aβ produced from these human neurons, it was shown that a more toxic type of Aβ is produced by the γ-secretase complex containing PS2. Furthermore, through specific immunocytochemical staining, it was found that the γ-secretase complex containing PS2 is mainly localized in late endosomes. These findings have made it clear that differences in Aβ production capacity can arise depending on the type of catalytic subunit of the γ-secretase complex and its localization within the neuron.
The results of this study have successfully demonstrated the diversity of the Aβ production machinery using a human neuron model, and it is anticipated that this will lead to drug discovery targeting only the γ-secretase complex subtypes that can produce more toxic Aβ.
The results of this research were published in the online edition of "eNeuro" on February 19, 2021 (US Eastern Time).
Please see below for the full press release.