The correction of neural functions in AD-NPCs through silencing the expression of mutated PSEN1 is consistent with the finding in a recent study that some of PSEN1 mutations are not simple loss of functional alleles with respective to the AD phenotype-associated biochemical pathway [28]. Moreover, that study suggests that γ-secretase activity is available in excess under the physiological conditions. Therefore, it is possible that certain FAD PSEN1 mutations may gain functions to produce pathogenic effects. Thus, reduction in the expression level of PSEN1 in AD-NPCs would possibly reduce the production of phenotype-associated molecules by the mutated allele, remaining the normal function by the wild-type allele. Supporting this notion, we found that over-expression of wild type PSEN1 in AD-iPSCs is not able to correct the premature neuronal differentiation of AD-NPCs. Thus, simply increasing dosages of PSEN1-WT could not prevent or correct mutated PSEN1-induced NPCs dysfunctions. In contrast, a reduction in the endogenous level of mutant PSEN1 is beneficial for FAD patients harboring PSEN1 mutations (Figure 5c-5g).
