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¹ Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan
² Organization for Pharmaceutical Safety and Research of Japan, Chiyoda-ku, Tokyo, Japan
³ Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
⁴ Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan
⁵ Brain Science Institute, RIKEN, Wako, Saitama 350-0198, Japan
⁶ Department of Demyelinating Disease and Aging, National Institute of Neuroscience, Tokyo 187-8502, Japan

The presenilin (PS) complex, including PS, nicastrin (NCT), APH-1 and PEN-2, is essential for -secretase activity. Previously, the PS C-terminal tail was shown to be essential for -secretase activity. Here, to further understand the precise mechanism underlying the activation of -secretase regulated by PS cofactors, we focused on the role of the PS1 C-terminal region including transmembrane domain (TM) 8 in -secretase activity. For this purpose, we co-expressed C-terminally truncated PS1 (PS1C) completely lacking -secretase activity and the PS1 C-terminal short fragment in PS-null cells, because the successful reconstitution of -secretase activity in PS-null cells by the co-expression of PS1C and the PS1 C-terminal short fragment would allow us to investigate the role of the PS1 C-terminal region in -secretase activity. We found that the exogenous expression of the PS1 C-terminal short fragment with NCT and APH-1 completely rescued a defect of the -secretase activity of PS1C in PS-null cells. With this reconstitution system, we demonstrate that both TM8 and the PS1 C-terminal seven-amino-acid-residue tail are involved in the formation of the active -secretase complex via the assembly of PS1 with NCT and APH-1.

^aPresent address: Department of Physiology & Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

^* Correspondence: E-mail: hkomano{at}nils.go.jp