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The presenilin (PS) complex, including PS, nicastrin (NCT), APH-1 and PEN-2, is essential for γ-secretase activity. Previously, the PS C-terminal tail was shown to be essential for γ-secretase activity. Here, to further understand the precise mechanism underlying the activation of γ-secretase regulated by PS cofactors, we focused on the role of the PS1 C-terminal region including transmembrane domain (TM) 8 in γ-secretase activity. For this purpose, we co-expressed C-terminally truncated PS1 (PS1ΔC) completely lacking γ-secretase activity and the PS1 C-terminal short fragment in PS-null cells, because the successful reconstitution of γ-secretase activity in PS-null cells by the co-expression of PS1ΔC and the PS1 C-terminal short fragment would allow us to investigate the role of the PS1 C-terminal region in γ-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 γ-secretase activity of PS1ΔC 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 γ-secretase complex via the assembly of PS1 with NCT and APH-1.