Clinical case study and functional characterization of the disease-associated presenilin-1 (PSEN1) mutations may help reveal the roles of PSEN1 in the pathogenesis of Alzheimer's disease (AD). By mutation screening of PSEN1, presenilin-2, and amyloid precursor protein genes in two Chinese Alzheimer's pedigrees, we identified two novel PSEN1 mutations, I249L and P433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on presenilin-1 endoproteolysis and beta-amyloid (A beta) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased A beta 42 levels and A beta 42/A beta 40 ratios. However, the I249L did not affect presenilin-1 endoproteolysis or A beta 43 production, whereas the P433S mutant inhibited presenilin-1 endoproteolysis and enhanced A beta 43 production. Our findings suggest that both I249L and P433S are pathogenic for early onset of AD by increasing A beta 42 production and A beta 42/A beta 40 ratios. Furthermore, P433S may contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer A beta peptide A beta 43. (C) 2019 Published by Elsevier Inc.