fig7

Figure 7. PS1 mutations (PS1: presenilin 1). Presenilin 1 is one of the four catalytic subunits of the γ-secretase protein complex^[50]. Over 300 PS1 mutations have been identified, covering ~ 25% of the PS1 residues, which account for the majority of FAD mutations^[40]. Most are missense mutations that localize in the TMDs and in the HLs. Upon assembly and maturation of the complex, presenilin 1 is cleaved within the large cytoplasmic loop into two fragments, the NFT comprising of TMDs 1-6 (blue) and the CTF comprising TMDs 7-9^[51]. Cleavage occurs between the two aspartate active site residues in TMDs 6 and 7 (labeled D)^[52]. The FAD mutation A2456 generated for the iPSC neurons in the mPS1 study^[24,25] is shown in red. FAD: familial AD; TMDs: transmembrane domains; HLs: hydrophilic loops; NFT: N-terminal fragment; CTF: C-terminal fragment.